Characterization and Physiological Activity of Some Kawa Constituents

R. HANSELl

Kawa, THE RHIZOM E OF Piper metbysticnm, hasplayed an impor tant role in the lives of thepeoples of Oceania. This paper presents a re­view of our current knowledge of the kawaconstituents- their molecular structure, theirpharmacological properties, and their chemicaland spectroscopic character.

AROMATIC CON STITUEN TS AND THEIR

PHYSIOLOGICAL ACTIVITY

Piper metbysticum Forster is a shrub in thefamily Piperaceae which occurs in Oceania. Itsstriking characteristics are long-stemmed, heart­shaped leaves, peculiarly knotty branches, andsmall flowers which lack a perianth and whichform a dense inflorescence reminiscent of earsof grain. It is one of the bisexual members ofthe genus; apparently, however, only plants withmale flowers exist. This necessitates vegetativeprop agation of the species. The original habitatof the plant is not known; perhaps it is NewGuinea. From the rhizome, less often from asprout, Polynesians and Melanesians preparethe so-called kawa, 'awa, or yangona drink,which is characterized by its peculiar sedativeand muscle-relaxing effects. In order to under­stand the role which the kawa plant played inthe life of these peoples one has to considerthe endemic character of the flora of theseregions. The flora of Oceania is markedly differ­ent from that of the Asian continent as well asfrom that of the American continent. Naturedid not provide the Polynesians with intoxicantsand stimulants of plant origin, substances of thetypes which were known to the peoples of Asia,Europe, and America. Most of the indispensablemedicinal agents-such as opium, hashish, cocaleaves, the Solanum drugs, digitalis, and Col­chicttm-of the peoples of the old world andof the American continent remained unknownto the Polynesians. N or did they have alcohol.

I Institute of Pharmacognosy, Freie Uni versitatBerlin , West Germany. Manuscript received June 13,196 7.

They knew only one stimulant which at thesame time was an effective medicine: 'awa . Ap­parently , 'awa for the Polynesians was a stimu­lant, an anesthetic, and an effective medicine.A plant of such importance, of course, alsoplayed a role in the religious life: kawa was thedrink at religious ceremonies.

If one summarizes the numerous reports inthe ethnological literature about the folk medi­cinal uses of the drug and translates them intomodern scientific language, the followingstriking properties of kawa emerge (Lewin,1886; Titcomb, 1948; van Veen, 1938) : (1 )It removes tension and anxiety. (2 ) It is ananalgesic. (3) Small doses relax the muscles ofthe extremities, while larger doses paralyzethrough relaxation, without, however, causinga decrease in consciousness or will power. (4)The reversible relaxation or paralysis of themuscles of the extremities is not as pron ouncedas it is with curare; it also probably acts on thecentral nervous system. ( 5) The drug is activeagainst various skin diseases. (6) Consumptionof kawa may lead to photophobia.

Modern research has dealt with two majortasks: first, to recognize which constituents areresponsible for the effects listed here; andsecond, to analyze the effects themselves throughstudies with experimental animals. The em­phasis in the following discussion will be onpharmaco-chemical considerations. Results ofpharmacological investigations will be treatedonly parenthetically.

Th e characteristic constitsents of kawa

If one chews a piece of kawa, the tip of thetongue quickly becomes numb, as if one hadchewed coca leaves. All of the early investiga­tors associated kawa with cocaine, the localanesthetic principle of Folia cocae, This associa- ·tion, later shown to be false, directed kawaresearch into certain channels. First, a beliefpersisted until very recently that kawa musthave nitrogenous principles (alkaloids) as doescoca. Every so often a report appeared which

293

294

claimed that alkaloids were actually demon­strated (only, however, on the basis of colorreactions), but actual isolation of nitrogenouscompounds has never been successful. The factthat the usual testing reagents for alkaloids arerelatively non-specific was not taken into ac­count. Especially ignored was the fact that thea-pyrones (which contain no nit rogen) canbehave similarly to alkaloids in some of thesetests (Farnsworth et al., 1962). Furthermore,L. Lewin, a toxicologist and pharmacologist inBerlin , who studied the drug intensively from1880 on, was able to demonstrate that theanesthetic principle could be extracted from theplant with fat solvents, such as petroleum ether.Since that time, pharmacognosists and chemistshave examined almost exclusively the lipid frac­tion of the plant.

MOLECULAR BUILDING BLO CKS O F THE kawaLACTONES (PYRONES): Nine lactones and twochalcones (i.e. , eleven aromatic compounds)have so far been isolated from the plant. N oneof these occur as glycosides. We shall first con­sider the lactones, all of whose structures followthe pattern shown in Figure 1. The basic skele­ton consists of 13 carbon atoms, 6 of them in abenzene ring. The benzene ring is linked by a2-carbon bridge to an unsaturated 6-memberedlactone. At first sight this lactone is reminiscentof sorbic acid lactones or of the bufadienolides

tR' nO

CH3'7 I 5 ~3

8 71R~CH=CH 6 02 0,FIG. 1. Common molecular skeleton of the kalVa

lactones and their hypoth etical pre cursor.

PACIFIC SCIENCE, Vol. XXII, July 1968

which are cardiac-active glycosides isolated fromthe plant genus Scilla and from toads. However,an important difference should be noted. Thekawa lactones contain a methoxyl group as partof an enol ether function, which strongly modi­fies the behavior of the lactone toward acidsand alkalies, as compared with the bufadieno­lides and other known (\-lactones. In the kawalactones we are dealing with masked enols of~-diketones. The chemical behavior of the kawalactones is summarized in Figure 2 using kawainand dihydrokawain as examples (B orsche et al.,1914-1933) .

NATURALLY OCCURRING STRUCTURAL VARI­

ANTS : We have seen that the characteristicconstituents of kawa are (\-lactones, which maybe considered to be a-pyrones bearing a me­thoxyl group at carbon 4 and an aromatic styrylor phenyl ethyl moiety at carbon 6. The questionarises what structural variants of this basicskeleton occur in nature. We can distinguishtwo groups of structural variants: (a) variancedepending on the degree of saturati on, and(b) variance depending on benzene substitu­tion.

(a ) We note that the molecule of the basicskeleton, the styryl-a-pyrone, contains threenon-aromatic double bonds. If one assumes thatin the biological environment, that is, in theplant, each of these three double bonds can besaturated independently, eight variants are con­ceivable which would differ from one anotherwith regard to the degree of saturation. The o­retically, there is no difficulty in synthesizing alleight variants. Nature, however, seems to followits own laws in that not all variants which aresynthetically available in the laboratory occurin the plant; a certain limitation or choiceexists. In our case the following situation ob­tains. The kawa plant lacks all those variantswhich contain the reduced double bond at car­bon 3. To put this positively, all naturally occur­ring kawa lactones invariably contain in themolecule the enolic double bond. The numberof structural variants which occur in the plantis therefore reduced to 4. Another phenomenonis present. The double bond at carbon 7 isreduced only when the double bond at carbon5 is also in the reduced state. These relationshipsare summarized in Figure 3.

Kawa Constituents-HANSEL

OCH3

O-CH~CH~Okawa in

cinnamalacetone

phenylvaleric acid

1 HZ,(Pd)..

HOBr

(') ~HJ

~CHz-CHz-lO~Odihydrokawain Cmarindin)

dih yd r o k o wo i c o c i d

6 - phenyl-hexan -Z-one

295

FIG. 2. Chemical reactions of kawain and methysticin (only kawain is shown) .

(b) Nothing very remarkable can be saidregarding the substituents on the benzene ring.In addition to unsubstituted derivatives we findthe corresponding p-methoxy derivatives, dime ­thoxy derivatives, and dioxymethylene com­pounds. No lactones occur in kawa which havea free hydroxyl group to which sugars could belinked to form glycosides . Lactones with a freeor a glycosidically linked hydroxy group there­fore do not occur. Of course we have no answerto the question why the kawa plant does notproduce free phenols or glycosides . This mayhave to do with the excretion cells of the plant.A particular constituent, in order to be de­posited in the excretion cells of the Piperaceae,must have a certain lipid solubility, a phenom­enon which is well known from the constitu­ents of essential oils. Substances with a freehydroxy group, or even with glycosidicallylinked hydroxy groups, obviously do not havea suitable partition coefficient for deposition inthe excretion spaces. Of course, the correlationmay also be reversed : since the plant synthesizes

many lipophilic end products, excretion cells areformed. Be that as it may, a correlation no doubtexists.

If we now combine the two possibilities forvariati on, (i) the degree of hydrogenation, thatis, the number of non-aromatic double bonds,and (ii) benzene substitution, we arrive at apossible total of twelve structural variants(Table 1) . Six of these have been known fora long time . We have worked out effective ana­lytical separation and testing methods which willallow us to find additionallactones which mightoccur in the plant in trace amounts . We havesynthesized all twelve structural variants and afew additional ones. Furthermore we have in­vestigated kawa from various parts of Oceania,using samples from the island of Hawaii, theFiji Islands, and from Samoa. As a result wenow have the following picture. In addition tothe six already known lactones we have demon­strated the presence of three add itional deriva­tives so that today nine of a total of twelvepyrones are known as constituents of Piper

296

Non-aromatic double bonds: 3

Theoretically possible variants : 8

not hydrogenated : 1

monohydrogenated(A3 or A5 or 1::. 7 ) : 3

dihydrogenated(1::. 3.5 or A3.7 or 1::. 5 .7 ): 3

fu lly hyd rogena ted : 1

Naturally occurring(not hydrogenated, 1::. 5 ,1::. 5.7 ) : 3

FIG. 3. Hydrogenation stages of the kawa lactones.

metbysticum (Klaproth, 1966). It is interestingthat in both series of the unsubstituted lactonesand of the p-methyl substituted ones we findthree degrees of hydrogenation. In the dioxy­methylene derivatives one of the stages ofhydrogenation is missing. It is the same onewhich, as the only representative of the series,occurs as a dimethoxy derivative. We do notknow whether this vicarious occurrence ofdirnethoxy- and dioxymethylene, or for thatmatter the entire a-pyrone spectrum of theplant, is the result of evolutionary coincidence,or whether some day we shall be able to under­stand this development on causal biosyntheticgrounds. However, let us not linger over fru it­less speculations regarding the origin of thepyrone spectrum, let us rather ask in which waythe plant constructs these substances. I shall notbe able to offer direct proof for definite bio­synthetic pathways since tracer studies or dy­namic biochemical studies have so far not beencarried out. The ideas of the biosynthesis ofthe kawa pyrones which I shall discuss arebased on a comparative study of molecularstructure and on reasoning by analogy whichhas derived justification from the fundamentalagreement in the metabolism of all green plants .

IDEAS ON THE BIOSYNTHESIS OF THE kawaPYRONES : let us consider briefly the structure of

PACIFIC SCIENCE, Vol. XXII, July 1968

the kawa pyrones from a biogenetic point ofview. It is striking that the benzene ring issubstituted in the manner in which we know itfrom the phenylpropyl compounds (cinnamicacids, lignanes, and coumarins) . The synthesisof these C6-Cs-compounds goes back to shiki­mic and prephenic acids. The remaining fourcarbon atoms in the molecule of the kawapyrones show two alternating oxygen functions,a feature which is characteristic of substanceswhose biosynthesis indicates polyacetate chains,that is, acetate metabolism. We thus arrive atthe picture that the kawa pyrones are an exampleof so-called mixed formation . They are formedfrom phenylpropanes and from acetyl coenzymeA building blocks and, if one considers num­bers, from one phenylpropane and two acetateunits :

C6-CS+ 2 C2 --? CIS (k awa pyrones)

Such a scheme is outlined in Figure 4. Naturalproducts which demonstrate such a mixed con­struction from phenylpropanes and acetates areno rarity in the plant kingdom. The most im­portant representatives are the flavonoids, whichare made up of one phenylpropane unit andthree acetate units (Geissman and Hinreiner,1952) .

C6-CS + 3 C2 --? CI5 (flavonoids)

The kawa pyrones therefore appear to benothing but variants of flavonoids. Of coursethis holds only if one considers the metabolicphysiological and not the analytical chemicalpoint of view, since no flavonoid-like C15­compounds are known with a-pyrone structure.Flavonoids and kawa pyrones seem to have acommon precursor . Kawa pyrones appear to beprecursors of flavonoids with one less acetateunit. It is very remarkable that it was possibleto discover in the kawa plant the pyrones which,so to speak, correspond to flavonoids, CIS­compounds which are analogs of C15-compounds(Fig. 5) (Hansel et al., 1963) .

Up to this point our biosynthetic schemeassigns to the kawa lactones a given position inthe flavonoid metabolism of plants. It does notexplain why only certain degrees of hydrogena­tion occur in nature . The following biosyntheticscheme combines the observation on the occur­rence of certain hydrogenation types and places

KaUJa Constituents-HANSEL

TABLE 1

STRUCTURAL VARIANTS OF THE K AWA L ACTON ES AND THEIR O CCURREN CE IN NATUREl

297

Benzene-Hydrogena tion Name

substitution65 67

0 ···- - demeth oxyyan gon in+ - kawain+ + dihydrokawain

H'C0'O.. - - yangonin *+ - As-dihydroyangonin )

+ + tet rahyd royangon in * )

H'C0XJt-... - - 11 - methoxyyangon in*)+ - - - -

H3CO + + - - -

<=0- - - - - -+ - methyst icin+ + di hydromethyst ici n

1 Symbols used : • Occurs in trace amounts in Piper metb yst icum ,- - - Does not occur in Piper metbysticum ,

it into a hypothetical biosynthetic scheme. Inthis scheme (Fig. 6) the paths which lead onone hand to kawain and on the other hand toyangonin branch already at the stage of the ~, 1)­

diketocarboxylic acid. Reduction of the I)-ketogroup to an alcohol leads after cyc1ization to theenolic kawain and dihydrokawain. Enolizationof the I)-keto group, however, followed by

cyc1ization leads to the dienolic yangonin . Inorder to arrive at the hypothet ical (syntheticallyeasily accessible, but not occurring in nature)7,8-dihydroyangonin derivatives, the long con­jugated system of yangonin would have to beinterrupted. One therefore suspects that hydro­genation of the double bond at this point is notpossible for energetic reasons. In the case of

sh ik imic orprephen ic ac id

kawa [octanes -

- a101I

...... C.:::-CH CHHz I-0:0- C=O-:? a II I I II OH

-0 ~ C=C-~

OH

! lOla

-0Y) 1_' ~-o~c-c-1Lo~o

- 2 acetyl - Co A

- methy l donator

FIG. 4. A hypothetical scheme for the biosynthesis of the kawa lactones.

298 PACI FIC SCIENCE, Vol. XXII, July 1968

C9+ C2---..~ C11

yangonin

---...... C13

~

•

¢ H3C-

----I~~ IIC-I

C=O

HOhoCH3

yOCH3

flavokaw in A

FIG. 5. Biosynthetic scheme for the formation of yangonin and a C-15 chalcone from a commonprecursor.

kawain, no long conjugated system is inter­rupted when the 7,8-double bond is reduced.Th e dihydrokawain derivatives indeed occurin nature.

Physiological Activity of Kawa PYI'oneJ

The most intensive study of the pharmacologyof the kaUJa pyrones has been carried out forsome ten years by a team at the PharmacologicalInstitute of the Univers ity of Freiburg under thedirection of H . J. Meyer. The most importantobservations on the effects of the kaUJa pyronesseem to be the following: intensification ofbarbiturate narcosis (Klohs et. aI., 1959; Meyer,1962); analgetic effect (Briiggemann andMeyer, 1963); local anesthetic properties(Meyer and May, 1964) ; anticonvulsive effects(Meyer, 1964; Meyer and Meyer-burg, 1964;Kretzschmar and Meyer, 1965) ; spasmolyticeffect (Meyer, 1965a) ; antimycotic effects( Hansel, W eiss, and Schmidt , 1966) .

I should like to make another general obser­vation on the relationship between pharmacody­namic activity of the different kaUJa pyronesand their constitution. As far as animal experi­ments are concerned the lactones of the yangonintype, that is the dienolides, seem to be-withinthe usual dosages and as compared with enolides-pharmacodynamically inert.

In the enolides the effective optimum variesas a function of the hydrogenation of thedouble-bonded carbon 7 and of substituti on inthe benzene ring together with a dependence onthe method of testing. For example kawain hasthe strongest effect as a local anesthet ic, dihy­dromethysticin as a spasmolytic, and dihydro­kawain as an intensifier of narcosis.

INTEN SIF ICATION OF BARBITURA T E N ARCOSIS

(Klohs et aI., 1959; Meyer, 1962) : When aph armacologist has the task of testing ph arma­cologically littl e investigated substances for cen­tral sedative pr operties, he will probably mea­sure first the toxicity of the substance and thenthe decrease in spontaneous motility. At a veryearly stage of the screening pr ocess he will checkwhether and in which way his substances willinfluence the effect of barbiturates. Substanceswith a cent ral paralyzing effect intensify theeffect of barbiturates and/or considerably pro­long the effect. Oih ydromethysticin ( OHM)possesses to a part icularly high degree this effectof intensifying barbiturate effects ( intensifyingnarcosis). Let me cite an example (Meyer,1962) . After application of 150 mg/kg ofhexobarbital sodium, white mice sleep on theaverage for 2 hours. If the animals are pretreatedwith 240 mg/ kg OHM, they sleep after the

Kawa Constituents-HANSEL

oII

/C,

0- CH2 CH2I I I.& CH= CH-CH C=O

" /OHHO

1CYclYZation~OH

O-CH=CH{\H 0 0

1methylat ion

0-'" H~H3.& CH=CH~()O~

H 0kawa in type

1· H2OCH3

O-CH2-CH2H~0dihydrokawain type

299

oII

/C""

0- CH CH2II II h CH=CH-C C=O

...... ~

OH HO

10yctyzobon

OH~

O-CH=CH-6-o 0

1 OCH3

0-: CH=CH--C:Lo 0yangonin type

+

H2t(interruption of the conjugation)

OCH3

0-'" 0.& CH2-CH2~o~o

7.8 - d ihydr oya ng on in type

(not found in the plant)

FIG. 6. Biosynthetic scheme show ing various stages of hydrogenation .

300 PACIFIC SCIENCE, Vol. XXII, July 1968

TABLE 2

RELATIVE ANALGETIC EFFECT OF DHM AND DHK(Condensed from Briiggemann and Meyer, 1963)

same dose of hexobarbital sodium for 27 hours .Enhancement of barbiturate narcosis is a prop­erty which is shared by a relatively large num­ber of substances with central sedative prop­erties. What is very impressive in the case ofOHM, however, is the magnitude of the effect.

ANALGETIC EFFECT : Together with Briig­gemann, a team under K. H . Meyer in thePharmacological Institute of the University ofFreiburg tested the analgetic effectiveness of thetwo kawa pyrones, 0 HK (dihydrokawain) andOHM. In the analgesic test according to Grossthese two substances prove to be comparable ineffect with dimethylaminophenazone. Theseresults are summarized in Table 2.

the most effective compound in surface anes­thesia is kawain which equals the effect ofcocaine in the cornea test. Kawain and cocainepossess the same limiting concentration (equalto the smallest concentration which causes com­plete anesthesia in all animals) and equallength of anesthesia. The kawa pyrones aresomewhat less effective in infiltration anesthesia.Of some interest for their evaluation is the factthat the kawa pyrones are very compatible withtissues and no danger of toxic resorption exists.

ANTICONVULSIVE EFFECTS : A cursory com­parison of the total effect of kawa on man andof the pharmacological activity of the pyronesin the animal shows that kawa acts predominant­ly by central paralysis. In order to characterizein greater detail substances having a centralparalytic effect, it is important to know towardwhich central nervous system (CNS) stimulantsthese substances act as antagonists. Furthermore,one needs to know whether they are capable ofinhibiting tonic or clonic spasm componentsof electric shock.

Concerning the inhibition of electric shock,a whole series of well known and excellentdrugs have been introduced into therapy andare frequently used as sedatives which inhibitat a given dose but which are toxic. A wellknown example of the statement that CNSsedatives are not necessarily effective inhibitorsof electric stimulation is meprobamate . Othersedatives enhance, contrary to expectation, eventhe readiness for contraction; an example isreserpine. According to investigations, whichagain were carried out by the Freiburg team,OHM and OHK are contraction inhibitors. Thisinhibitory effect is qualitatively and quantita­tively comparable with that of phenobarbital,pyrimidone, or diphenylhydantoin. Animal ex­periments have shown that OHM in particularmay be considered a strongly effective anti­convulsant.

The behavior of the two kawa pyrones ispeculiar toward chemical convulsive toxins,toward bemegride, pentetrazole, picrotoxin, andstrychnine. Figure 7 shows the following: (i)Tonic bemegride and pentetrazole convulsionsare activated within a given dose range (pre­administration of 20-45 mg/ kg OHM) . (ii)Tonic picrotoxin and strychnine convulsions are

2.5100120140200

DOSE (rng/kg)

LOCAL ANESTHETIC PROPERTIES : I have men­tioned earlier that chewing crude kawa anes­thetizes the tip of the tongue. This anestheticeffect is caused by OHK, a fact which has beenknown for a long time (van Veen, 1938).Again it was H. J. Meyer and his collaboratorswho carried out the detailed study of the localanesthetic properties using the testing methodsof scientific pharmacology. It was shown, first,that not only OHK but that all the other kawapyrones possess local anesthetic properties; how­ever, not all pyrones have an equally strongeffect. It was further demonstrated that thepyrones developed superficial anesthetic as wellas infiltration effects. I shall mention a few de­tails of the experiment on surface anesthesia(rabbit cornea) and the results. Most effectivewith respect to the degree of hydrogenation arethe L 5-dihydro derivatives, followed by theL 5,7-tetrahydro derivatives; the non-hydro­genated yangonin homologues are ineffective.Unsubstituted derivatives are more effective thandioxymethylene substituted ones. Accordingly,

ANALGETIC AGENT

morphinedimethylaminophenazonedihydrokawaindihydromethysticinacetylsalicylic acid (a spirin)

Kallla Constituents-HANSEL 301

well known antagonism of phenobarbital towardstrychnine.

If in conclusion we ask to which long-usedtherapeutics the kallla pyrones show the greatestsimilarity, we may quote H . J. Meyer who, inconsidering recent results which are not repro­duced here, says, "Aside from certain peculiar­ities of their action the kallla pyrones show thecharacteristics of two anticonvulsants which havelong maintained a leading role in epilepsytherapy, diphenylhydantoin and phenobarbital.The similarity with the action of diphenylhy­dantoin is somewhat more pronounced."

SPASMOLYTIC EFFECT : Oihydromethysticinwas tested thoroughly for its spasmolytic action.In all experimental designs with smooth muscleorgans and with organ systems, it proved moreor less effective. An inhibition of spont aneousactivity as well as a relaxing effect on muscletone could be demonstrated. The mechanism ofthe action was predominantly designated asmusculotropic (similar to papaverine) .

ANTIMYCOTIC EFFECT : Anyone who hasworked in a laboratory with aqueous plant ex­tracts has observed that , if these aqueous plantextracts stand around for some time, they spoil.The extracts become inhab ited by microorgan­isms. We observed some time ago that aqueousextracts of kallla do 120t spoil, at least not whilethey contain traces of kallla pyrones. In collabor­ation with the Institute of Hygiene and Bac­teriology of Freie Un iversitat Berlin we havestudied the bacteriostatic pr operties of the kalllapyron es. The data (Table 3) are not completesince the investigations have not terminated.I shall mention the following preliminary reosuIts (Hansel, Wei ss, and Schmidt, 1966).

(i) The kallla pyrones do not act as bac­teriostats. A large number of gram positive,gram negative, pathogenic, and apathogenicbacteria were tested and they developed unin­hibited in nutrients containing pyrones.

(ii) On the other hand, certain kallla pyronesshow remarkable fungistatic effects. It is wellknown that there exists a large number ofbacteriostats but only a very small number ofsubstances which are capable of inh ibiting thegrowth of fungi. Among the fungi which showa high sensitivity part icularly toward OHK are

90 10010 20 30 40 50 60 70

mg/k g OHM i.p.

......... 50 bemegr ide0--0 120 pen te t rc ac le____ 6.5 picrotoxin~ 1.5 str ychn ine... - -.. elec tr ic convulsion

30mA, 60 Hz, 0.2 sec

10

20

30

90

50 t:::>'ro:::;..,~""+_---_t\\_---+__---__l

60

70

80

40

l00r-- - - .,.-- - - ,.-"- - - -.-- - _ -,

FIG. 7. Ant iconvulsive activity of D H M ; convul­sions produced experimentally by various agents(M eyer, 1964) .

inhibited by preadministration of OHM, whichis similar to electric convulsions. Strychnineconvulsions are inhibited more strongly than arepicrotoxin convulsions.

The curves would look very different if theinh ibition of clonic convulsions had taken placeinstead of tonic convulsions. T oward clonicconvulsions, which appear after app lication ofthe above-named convulsive toxins (bemegride,pentetrazole and picrotoxin) preadministrationof O HM has essentially no effect. On the con­trary, OHM enhances and prolongs strikinglythe clonic convulsion phase . Especially by ad­ministrati on of OHM one effects long lastingstrong convulsions with only rare and short­lived convulsion pauses (with out OHM the con­vulsions show a more seizure-like character) .The two kallla pyrones OHM and OHK (thelatter has a weaker effect) are therefore capableof suppressing only incompletely the convul­sions caused by chemical convulsive toxins sincethey can suppress only the tonic but not theclonic component. A remarkab le exception isstrychnin e. In this case OHM and OHK are ableto supp ress both types of convulsion. It may besaid that both pyrones demonstrate a definiteanti -strychnine effect, which even surpasses the

302 PACIFIC SCIENCE, Vol. XXII, July 1968

CHEMICAL AND PHYSICAL PROPERTIES

O F THE Kawa LACTONES

o

Ar - CH=CH~OCH3

yang on in t ype(old ( -pyrone fo r mu l a , Bors che , 1914)

Chemical Behavior

The characteristic constituents of kawa may beclassified into two main groups. The first group ,of which kawain is an examp le, is characterizedby a single doub le bond in a 6-memberedlactone ring . The second type, of which yangon­in is an example, belongs to the series of die­nolides . H owever both types may be consideredeither 6-membered lactones or 6-styryl-a-py-

0.0 20.00 80 .005

0.00 5

0 .0050.0050.00 35

g/ ml

0.0 50.03

0.00 30 .00 3

0.001(+ )

(+)(+)( + )(+ )( -)(-)(-)(-)(-)(-)

ecc pyr o n a

o

Ar - CH= CH~OCH3"(-p yr one

o

- ~Ar - CH.CH-lL 0 ),.0

TE ST ORGAN ISMS

I NHIBITION OF S OME F U N GI AND StreptomycesORGANISMS BY POWDER ED KAWA RHIZOlvlES 1

TABLE 3

Tricbotbecium roseumAlternaria consortialePenicillium [unicu losum

(potential hu man pat hogen)A ltern aria humicolaStreptomyces griseusCrytococcus neojormans

(human pathogen)Trichophyton tonsurans

( hum an pat hogen)Streptomyces purpurescensPaecil omyc es variotiAsp ergillus niger

(p otentia l human pathogen)Cbaetomiu m globosumT richophyton [errugineum

(human path ogen)Botrytis cinereaScopulariopsis breuicaulis

(p otent ial human pathogen)Saccharomyces cereoisiaeAspergillus tamariiA spergillus flavusFusarium solaniCandida albicans (human pathogen)Candida kruseiCandida parakruseiCandida parapsilosisCandida tropicalis

1 The num bers are the rmnrrnurn concen trat ions (g ) ofkawain per volume (ml) nutrient which completely inhibitmacroscopicall y visible development of the fu ngus. ( +)Indicates only grow th inhibition at a concen tra t ion of0 .05 g / rnl. (-) Indicates no effect at a concent rat ion of0.0 5 g/ rnl. (Hansel et al. , 1966 ) .

correct formulat ion of yangonin. Methylationof the styryl substi tuted with triacetolactone(yangonalactone) with diazomethane leads totwo isomeric methyl derivatives, one of whichis identical with the natu ral product. T he ques­tion remains which of the two isomeric methyltriacetolactones is identical with the naturalproduct, the a - or the y-pyrone. Borsche (1914)

EH3

I '"Ar-CH=CH 0 0

ya ng on in ty pe{dlencli de , Bu't ock t Smi th . 1960jChmielews ka €'J gl. 195 8 )

OCH3

Ar-cHoCHO okaw ain type

such rugged types as Aspergillus niger. Perhapsthe best known antibiotic which is effectiveagainst fung i is griseofulvin and it has absolutelyno effect on A spergillus niger.

(iii) The effect of the pyrones is very selec­tive. On ly certa in genera of fungi, often onlycertain species, are attacked. Among the fungiwhich are completely untouched are the yeasts-pathogenic forms as well as the ancient wineand beer yeasts. Further investigations are de­signed to show whether among the fungi whichare affected by the kawa pyrones are generawhich are pathogens in man .

rones. The recogn ition that yangonin also pos­sesses lactone character is however rather recent( Chmielews ka et al., 1958 ) . Earlier it was con­sidered a y-pyro ne and accordingly two seriesof characteristic kawa const ituents were differ­entiated , the a -pyrones (lac tones) and the y­pyrones. It is obvious that the structura l elucida­tion of yangonin provided some difficulties. Inorde r to demonstra te these peculiar difficult iesit is more useful to outline a synthesis of yan­gon in start ing from the dimethyl derivative(yangonalactone) rather than to trace the his­torical development which eventually led to the

Kawa Constituents-HANSEL 303

TABLE 4

1 ChmieIewska et al ., 1958; Bullock and Smith, 1960.2 Alder and Rickert , 1937.

SOME DIAGNOSTIC TESTS TO DISTINGUISH BETWEEN

TAUTOMERIC u- AND y-HYDROXYPYRONE

METHYL ETHERSI

chose a y-pyrone formulation for the followingreasons.

By the action of alkali under mild conditionsyangon in can be saponified to an acid andmethanol, analogous to a methyl ester of acarboxylic acid. Kawain, on the other hand, theconstitution of which was secured as an a­pyrone, behaved differently . Under analogous

ester of yangona acid." Borsche 's ideas aresummarized in Figure S. If we consider Bor­sche's yangonin formula in some detail, we arerather surprised that the following points didnot concern him .

(a) Ring opening with alkali is generallyeffected more easily with a -pyrones than withy-pyrones.

(b) Borsche's yangonin formula has thestructural characteristic of an enol acetal. Acetalsare generally more resistant to alkali than areesters and vinylogous esters (enol ethers) . Itappears to me that it would have been possibleto arrive at the opposite conclusion that thealkali liability of the ring demands formulationof an a-pyrone.

In 1954 a Polish team reopened the questionof the structure of yangonin. They systematic­ally synthesized a-pyrones and the analogousy-pyrones and investigated both types of com­pounds with IR and UV spectroscopy. IRspectroscopy in particular proved to be an ex­cellent aid for distinguishing between the twoisomeric pyrones . All y-pyrones showed acarbonyl band at 6.0f! (1667 crrr"}, while thea-pyrone band appears at 5.Sf! (1724 crrrt ) ,which is the characteristic band of unsaturatedlactones.

These investigations made it apparent thatthe pyrones which occur in the kawa rh izomediffer from one another by thei r substituentsand by their degree of hydrogenation, and not,

+

++

+

+

4-METHOXY- 2-METHOXY-

y-PYRONE y-PYRONE

OH

0~oCH30H + Ar-cH=cHJ!.. 'b ~

• OH ' OH

owy c nqonf n

Basicity(a) ether-insoluble

oxonium saltform ation

(b) picrate format ion

IR carbonyl frequency(a) 1724cm- l

(u-pyrone )(b) 1667cm- l

(y-pyrone)

Diels-Alder reaction-

TEST

conditions kawain furnished no methanol, nordid kawaic acid which was produced by actionof alkali. Borsche attempted to explain thisstriking difference in the behavior of kawainand yangonin in the following manner. Sincethe enol-ether linkage of kawain is not saponifi­able, yangon in, which splits off methanol readily,cannot contain an enol-ether linkage. He there­fore searched for a formula of yangonin whichwould combine an ester-like bound methanolwith a cyclic structure (differing by one mole ofwater from an open chain ester). Borsche for­mulated yangonin as a y-pyrone, which he alsoconsidered to be the "anhydride of the methanol

OH

Ar-cH'=cH~""OOH 'OH

yangona ac id

1CHZNZ

OH

Ar .cH=CHn::.O

OH OCH3me thyl yan gona t e

o

~ 0Ar-CH= CH-li. OJlOCH3

Bors che ls ya ngonin

FIG . 8. Borsche's argument for the structure ofyangonin.

304

as was originally assumed by Borsche, by beingcyclic isomers (u- and y-pyrones) . If the newyangonin formula is correct, it should be possi­ble by hydrogenation of the two double bondsto transform yangonin derivatives into dihydro­kawain derivatives. We (Wemy and Hansel,1963) were able to demonstrate that this isindeed possible. Starting with naturally occur­ring yangonin we obtained by catalytic hydro­genation p-methoxyd ihydrokawain , the constitu­tion of which was secured by an independent

PACIFIC SCIENCE, Vol. XXII, July 1968

synthesis. These reactions are shown in Figure9. One of the two double bonds in the ring isnot attacked under the given conditions (pal­ladium on carbon in ethyl acetate) . This agreeswith the observation that enol-ether doublebonds are catalytically hydrogenated only withdifficulty.

The actual cause, that is the mechanism, of thephenomenon which led Borsche to the wrongformulati on of yangonin is still not known. Whyis the enol-methyl ether of yangonin readily

p - meth oxy cinnamaldehyde

OCH 3I

.....C~H C'" "=CH

2 1 1

Br .....C~o 0I

CH313 - metho xy- t -bromo­crotonic acid methyl

es ter

1Mol HZPd in HOAc( ~Z m in" 65°)

Zn (Reformatsk y)

in tetrahydrofuran

OCH3

H~O~CH~CH~op - methoxykawain

HZ, Pd in methanol

( "'ZOmin . , 18°)

HZ' Pd in HOAc( .... Z hr.. 65° ) OCH3

H3co-O-CH2-CH2~O5.6.7.8 - tetrahydroyangonin

FIG. 9. Transformation of yangonin in 5.6.7.8-tetrahydroyangonin and its identity with synthetic (±) p­methoxy-y.Bvdihydrokawain (Werny and Hansel, 1963).

Kawa Constituents-HANSEL

saponified and methanol split off only with diffi­culty in the case of kawain? W e may reduce thisquestion to that of the alkali stability of the enolethers of the two homologous acids (see formu­las) .

C6H 5- CH =CH- C(R) =CH-C(OCH 3 ) = CH- C0 2H

OH-R = H (kawaic acid) --7 no methanol

OH-R = OH (yangona acid) --7 methanol

Spectroscopic Characterization of the KawaLactones

So far in this paper we have seen that thecharacteristic constituents of kawa are substi­tuted 6-membered lactones which may be classi­fied into two main groups, with one or twodouble bonds in the ring, the enolides and thedienolides. We have seen further that these twomain types may be distinguished by their be­havior during alkaline hydrolysis. In the follow­ing section we will show that recognit ion of thehydrogenation type is achieved more quicklyand more smoothly with the modern methodsof IR, UV, and mass spectrometry .

IR SPECTRA (Hansel, Rimpler, and Lang­hammer, 1966): It is best to start with twosimple model compounds, the methyl-triacetylacid lactone and the dihydromethyltriacetyl acidlactone (DH-MTL) , which we prepared forthe first time. The IR spectra of these two modelcompounds are exceedingly clear in the region ofcarbon-carbon double bond frequencies. DH­MTL exhibits in this region a single strong bandat 1622 crrr! which accordingly has to be as­signed to the enolic double bond at ~ 3 . In MTLthis band-probably because of conjugation ofthe two carbon-carbon double bonds-is shiftedtoward longer wave numbers by 26 crrr". W etherefore assign the band at 1566 cm-l to thedouble bond at ~ 5. The assignment of oneof the two hydrogenation types is also possiblewhen the lactone rings are substituted by styrylor phenylethyl radicals. The band at 955-966crrrt, which shows a trans CHR = CHR link­age, is well suited for the determ ination whetherwe are dealing with a styryl or a phenylethyltype. We dealt with a total of four hydrogena­tion types for which we were able to develop

305

a simple infrared assignment scheme as shownin Figure 10. The relationships are simplifiedand numerous details are omitted.

MASS SPECTRA OF THEkawa LACTONES (Paileret al., 1965 ): Compounds of the yangonin type(Fig. 11) are best discussed first. We are deal­ing here with a conjugated system. There is nopoint in the molecule which facilitates the for­mation of energetically favorable fragments.W e therefore find in this type of compoundlarge molecular ions and little fragmentation.Repeated elimination of 28 rn/ e corresponds totwo carbon monoxide molecules, which has beenobserved with coumarins. This is followed byelimination of a methoxyl group (rn /e 157,129) . If we now proceed to the compounds ofthe kawain type (Figs. 12, 13) , we notice theappearance of a peak which may be consideredan elimination of cinnamaldehyde. In additionthere is a peak which corresponds to the rest ofthe molecule which remains after cleavage ofcinnamaldehyde (M - 132) = 98. In th iscase cinnamaldehyde represents only a smallfragment while the fragment correspond ing toaldehyde minus hydrogen is larger. This how­ever is not true with the substituted derivatives.In these cases the aldehyde peak is of consider­able magnitude and no carbon monoxide elimina­tion takes place, which is observable in the un­substituted derivative. Furthermore, the intens­ity of various peaks is somewhat dependent onthe substitution pattern of the aromatic part ofthe molecule. The most striking peak in thespectrum of the compounds of the kawain typeis the peak which corresponds to a benzyl or atropylium ion. This means that quite unex­pectedly cleavage takes place at a double bond .Thi s is supposedly an artifact since pr esumablymigration of the double bond precedes cleavage.N everthel ess, one can consider the possibility ofa formal cleavage at positions with doublebonds in the interpretation of the mass spectra.With substitution in the benzene ring the frag­ment is correspondingly displaced , that is, it isan indicator for the correct interpretation.

Finally, there remains the inte rpret ation ofsubstances belonging to the dihydrokawain type.It proceeds normally with formation of a tropy­lium ion. Cleavage p is the normal reaction ofsaturated lactones.

306

(0)OCH3 1648 cm-1

15660m,-KH3C 0 0

MTL

PACIFIC SCIEN CE, Vol. XXII, July 1968

~1622cm-l

H~~H3C H 0 0

dihydro - MTL

R

---c OCH=CH-

styryl -

O~ CH -CH­- 2 2phenylethy l-

styryl-

pheny le thyl

1560 -1575 cm-1

+

+

RCH-CHR (trans)t'(CH)

955 -966 cm- 1

+

+

(c) OCH3

O-CH:CHOO

1800 1500 1800 1500 1800 1500 1800 1500

FIG. 10. In frared spectra of the kawa lactones. (a) Assignments of cyclic doub le bonds ; ( b ) influenceof side chain ; ( c) partial spectra.

UV SPECT RA (Hansel et al., 1967): Againit is best to begin with the basic lactone chromo­phore, the dihydromethyltriacetoacid lactone( DH -MTL). We are dealing here with ans-t rans-fi xed enone system, comparable to that

of parasorbic acid ( PSS) . DH-MTL differsfrom PSS in the position of the maximum byan increment of 30mfl, an effect which can beascribed to the ~-methoxy substituent (Fig. 14 ) .The magnitude of the increment is in good

Kawa Constituents-HANSEL 307

M22 8

69 Tl '103

01

157

200 ** ,.....- ---1-co

80 100 120 140 160 180 200 220 240 260 m/e

FIG. 11. Mass spectrum of dimethoxyyangonin (Pailer et aL, 1965) .

H

Q

98

M230

68

v.

77

91M- 126

104

115

M-99.131

20201 *-co

80 100 120 140 160 180 200 220 240 26 0 m/e

FIG. 12. Mass spectrum of kawain (Pailer et al., 1965) .

agreement with observations on other openchain enone systems. Since the enone systemexists in the ring, where it is rigidly maintainedin the energetically favorable s-trans conforma­tion, the position and magnitude of the absorp­tion change only insignificantly when we go

to the corresponding open chain enone system.In other words, we can compare PSS with cis­crotonic acid and dihydromethysticin (DHM)with tetrahydromethystinic acid (Fig. 15).

If we substitute the ring of DH-MTL witha phenylethyl or with a styryl radical instead of

308 PACIFIC SCIENCE, Vol. XXII, July 1968

135

M276

M-115161

131127

100 120 140 160 180 200 220 24 0 260

FIG. 13. Mass spectrum of dihydromethysticin (Pailer et aI., 196 5) .

280 m/e

FIG. 14. UV absorption of parasorb ic acid (a)and of dih ydro-methyltriacetic acid lactone ( DM­MTL) ( b) .

FIG. 15. UV absorp tion of parasorbic acid (a) ,cis crotonic acid (b), dih ydromethysticin (c) , andtetrahydromethysticinic acid (d) .

a methyl group, we obtain two groups of naturalkaUJa pyrones, the kawain and the dihydro­kawain types. In the naturally occurring dihydro-

HI

A _ H C,C"C-H,ln~- s . trQn5 3 I - s- lro n5

H3C 0 0 HO-C~O

Amax 205 m~ Aina x 205.5 m~

(l ag E= 4.03) (lag E = 4 .13)

a b

?CH3

<on -6~/,-,,<a nXJL' '" CH~"C- H

I I I l - s -tronso ~ CH2- CH2 0 0 ~ CH2-CH2-CH~eF"0

Amax 235 m~ Amax 234 mp(lag E = 4.19) (lag E = 4 .23 )

d

H3Ci)a"max 205 mfJ( Io q E. =4.03)

a

OCH3

H3C~O"max 235 mfJ( log E. = 4 .10)

b

kawains, the two part chromophores-the ben­zene ring with its variable oxygen functions andthe DH-MTL moiety- are separated. The spec­tra of these substances may therefore be in­terpr eted as addition spectra of the two partialchromophores. This is grap hically demon­strated in Figure 16 for the spectrum of tetrahy­droyang onin (p-cresol methyl ether + DH­MTL) . In contrast to the compounds of thedihydrokawain type we may consider that in thenaturally occurring kawains the two part chromo­phores (styryl and DH -MTL moiety) have amutual effect on each other . In spite of this it issurprising that the spectra of this class of com­pounds are also additive from given partialchromophores, that is, they may be predicted bycalculation from the corresponding cinnamylalcohols and the DH-MTL. On the other hand,measured and calculated spectra do not agreewhen , instead of the cinnamyl alcohols, thearomatic chromoph ore is represented by otherstyeyl derivatives, such as allyphen ols of theanethole type.

A second large group of kaUJa lactones arenot derived from DH-MTL but from MTLitself . The two parent substances differ fromeach other by a double bond in the lactone ring.The enone system is extended to a dienone

KaUJa Constituents-HANSEL 309

1C")

I

o

oE

'-0

20

15

10

5

OCH3

a H3C0'O- -6-0--0--0- I .& CH2-CH2 0 0

.'.'.

1 H3CO~.-

...~ -l:r-~-l:r- Ih CH

3

'. OCH3

2

H~JX-+._+ ._+.-'.

,,- .~

,,- \I .

I~,

b = 1+ 2I ..• .. .•...•..

I~.+ ~

I .'~

J.-~,/1 \\I \

\\\\\

~\

\\\\\\\ ~........ ..

. -t:.-~ ,-~,

~\ . '" ""'0'

b. '" b.'"\ '- _-6--- -~:"

" ...... ....... -220 230 240 250 260 280

7t. [nmJ -FIG. 16. UV spectra of (a) tetrahydroyangonin, and (b) the addition spectrum of (1) p-cresol methyl

ether + (2) DH·MTL.

310 PACIFIC SCIENCE, Vol. XXII, July 1968

FIG. 17. UV absorp tion data of the MTL system.

system (Fig. 17) . Generally, extens ion of anenone by an additional conjugated double bondcauses a bathochromic shift of 30mfl and an in­crease of the extinction coefficients in the UVspectra. In our case, the transition from DH­MTL to MTL, the increment is 45mfl and thechange in intensity is in the opposite direction,that is, it is a decrease (hypochromic effect).Doubtless this apparent anomaly depends on thefact that the new double bond , which is part ofthe plan ar (pseudoaromatic) 6-membered ring ,exists in the high energy s-cis-conformation. Inagreement with this is the striking change in thespectrum when we compare substances withthis cyclic chromophore with those which pos­sess a formally identical but open chain chromo­ph oric system. We are dealing here with a tran­sition of a cyclic chromophore (with referenceto the CCC5 single bond) which has s-cis­conformation to an open chain chromophorewith the energetically preferred s-tram-confor­mation (Fig. 17) . Changes of conformation ofthis kind which we have postulated have thedescribed effect on UV absorption. If we sub­stitute a hydrogen atom in the methyl groupof MTL, we arrive at a 2 w DH-yangonin, whichis a type of kawa pyrone that is readily accessibleby synthesis but has not been found in nature.The UV spectra of these compounds are againadditive from the partial chromophores of MTLand substituted toluenes.

The last group of structural variants withrespect to degree of hydrogenati on is the onein which the lactone ring is connected with thebenzene ring by an ethylene bridge. The bestknown representative of this gro up is yangonin(R] = OCH3 , R2 = H ) (Fig. 18) . Since we

Ama x 235 m~

(E = 12.500)

S-ciS~3

RY-O~O7.8 - d ih ydro -5.6-dehydro ­

rne thysti c !n

"max 285m p ( E = 11.200 )

e-els OCH3~ ... s - tra n s

)l"J:H3C 0 0

" max 280 m p

(£ = 6.000)

s - tra ns OCH3

R~HO 0

dihydromet h icinic acid

" max 272 mp ( E =20.250)

are now dealing with a fully conjugated system,the spectra are no longer simply predictable frompartial spectra. The increment ( ~/,) of thebathochromic shift is 164mfl for the styrylradical in MTL, and the factor for the enhance­ment of the intensity of the band is approxi­mately 4.4. The dienolide ring is certainly planarand we may formulate it as a pseudoaromaticsystem. With regard to position and intensityof the absorpti on band the pyrones agree withopen chain triene acids as long as one takes intoconsideration the different conformations; how­ever they differ markedly fr om the sepectraof the analogously substituted stilbenes. Figure18 shows further that spectra of triene acidsand of their methyl esters do not agree withrespect to position and intensity of the bands.Possibly the ester consists of mixtures of s-cisand s-trans conformers with respect to the singlebond between the carbonyl carbon and theadjacent carbon. A study of models of thesecompounds, however, lends no support forpossible steric hindrance.

CO N CLUS IONS

From the rhizome of Piper metbysticum orkawa a number of constituents have beenisolated which are characterized by remarkableph armacodynamic properties. One may ask whythese substances with such remarkable propertieshave not found any use in modern therapy, forexample, as an ataractic or an anticonvulsant.A precise answer to this question is not par­ticularly easy. There are available a large numberof chemical compounds, particularly among thereadily available synthetic ones, which inhibitthe central nervous system. Testin g methods forsuch compounds are well worked out and areplent iful. The probability of finding thera­peutically useful substances, therefore, is rel­atively great. This is particularly so since thesedative-hypnotic-narcotic property of a sub­stance is not structurally specific. In fact, allsubstances with a given physical-chemical prop­erty, for instance, a given par tition coefficient(relatively high lipid solubil ity) , represent po­tential sedative-hypnotic agents. This means thatin the case of hypn otic-narcotics one is not verydependent upon models in nature as is the casewith other groups of drugs. T o th is must be

Kawa Constituents- HANSEL 311

+

*

.."* +. .

*.

""+ *.+ '. '" .~

'..,"~ ~. .. .~ \: t. .. .

~..

'.

* .:-:~

* """

.-'.: It.!'

•

R'= R2 = H' R3=OHI

,,*..-2 ..*. R' = R2 = -a- c Hi 0- ; R3= OH

..+.. .~.. .+.. R' = R2= - O- CHr O-; R3=OCH3

R~ ~H3R~CH=CHJ!.O~O

1... , R'=R2=H .

R'O- OCH3. I <:>0R2 I h CH=CH-CH=CH-C=CH-C'R3

2......... ....

30

40

oE

\0

I

210 250 300

1\ [nmJ~

350

FIG. 18. UV spectra of the yangoni n type compo unds and their open chain analogs.

312

added that we expect newly introduced thera­peutics to be in some way superior to those whichare already in therapeutic use. It appears thenthat such superiority has not been demonstratedfor the kawa lactones.*

The further question arises: What is theintrinsic value of such a detailed investigationof the phytochemistry and pharmacology of asingle plant? I shall not retreat by respondingthat every scientific investigation, regardless ofthe subject or the goal, carries with it its ownjustification. I should like to express the viewthat there is scientific justification in learningthe chemical composition and the effects of anexotic plant which has played such an importantrole in the lives of the peoples of Oceania forthousands of years. To this may be added thatnatural products have always been models andexamples for new medicinal agents in bio­chemical research. Even if this is not the case,as has been pointed out, for the sedative-hypno­tic effect, it may perhaps be true for the othereffects of kawa. Perhaps the kawa pyroneswill stimulate chemists studying syntheticmedicinal products to new research in the fieldsof epileptic agents, endoanesthetics, or oralantimycotics.

I should like to thank the Chemistry Depart­ment of the University of Hawaii for the op­portunity to work in the chemistry laboratoryduring 1961 and Professor Paul J. Scheuer forhis assistance with the preparation of the En­glish manuscript.

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BRUGGEMANN, F., and H. J . MEYER. 1963. Dieanalgetische Wirkung der Kawa-InhaltsstoffeDihydrokawain und Dihydromethysticin.Arzneimittelforschung 13 :407-409.

BU'LoCK, J. D ., and H. G. SMITH. 1960. Py-

* In Germany, recently , kawain has been in­troduced into therapeutic use because of its muscle­relaxant and endo-anesthetic activity.

PACIFIC SCIENCE, Vol. XXII, July 1968

rones. Part 1. Methyl ethers of tautomerichydroxypyrones and the structure of yan­gonin. J. Chern. Soc. 103:502-506.

CHMIELEWSKA, 1., J. CIESLAK, K. GORCZYN­SKA, B. KONTNIK, and K. PITAKOWSKA.1958. Structure de la yangonine. Etudespectrographique dans 1'ultraviolet et I' in­frarouge. Tetrahedron 4:36-42.

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HANSEL, R., 1. LANGHAMMER, and H. RIM­PLER. 1967 . Analytische Studien an Kawa­Laktonen: UV-absorptiometrische Untersuch­ungen. Arch. Pharm. 300(2) :157-168.

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HANSEL, R., H . RIMPLER, and 1. LANGHAM­MER. 1966. IR-Spektren der a -Pyrone vomYangonin- und Kawain-Typ und Synthesevon 4-Methoxy-5 ,6-dihydro-6-methyl-pyron­2 als Modellsubstanz. Z. anal. Chern.218(5) :346-353.

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KLAPROTH, 1. 1966. Adsorptionschromatogra­phie lipophiler Naturstoffe an Aktivkohle:Begleitpyrone im Kawa-Rhizom (Pipermetbysticum Forst.) . Dissertation. Berlin . 91pp.

KLOHS, M. W ., F. KELLER, R. E. WILLIAMS,M. 1. TOEKES, and G. E. CRONHEIM. 1959.A chemical and pharmacological investiga­tion of Piper metbvsticum Forst. J. Med.Pharm. Chern. 1(1) :95-103.

Kiuo« Constituents-HANSEL

LEWIN, L. 1886. Piper m etbysticnm. Mono­grap hie. Berlin . 60 pp .

MEYER, H . J. 1962. Pharmakologie der wirksa­men Prinzipien des Kawa-Rhizoms (Pipermetbysticum Forst. ). Arch. intern. Pharm­acodyn. 138(3-4) :505-536.

- - - 1964. Un tersuchungen tiber den anti­konvu lsiven Wirkungstyp der Kawa-PyroneDihydromethysticin und Dihydrokawai n mitHilfe chemisch indu zierter Krampfe. Arch.intern. Pharmacodyn. 150(1-2) :118-13l.

--- 1965a. Spasmolytische Effekte vonDihydromethysticin , einem Wirkstoff ausPiper metbysticum Forst. Arch. intern. Phar­macodyn. 154(2) :448-467.

--- 1965b. Ant agonistische Wirkungengenuiner Kawa-Pyrone bei experimentellenEntzundungen und Fieber. Klin . Wsch r.43(8) :469-470.

MEYER, H . J., and M. DIERSTElN. 1965. Zurantagonistischen Wirkung von Pyron-Verbin­dungen des Kawa-Rhizoms (P iper 1Ilethy­sticnm Forst.) gegen 1,4-Dipyrrolidin o-2­butin. Arzneimittelforschung 15: 1344-1347.

MEYER, H. J., and R. KRETZSCHMAR. 1965.Kawapyrones-group of components in cen­tral muscle relaxing agents of the mephenesintype. N aunyn-Schrniedeberg 's Arch. expoPath . Pharmakol. 250(2) :267.

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MEYER, H. J., and J. MEYER-BuRG. 1964.Hemmung des Elektrokramp fes durch dieKawa-Pyrone Di hydromethysticin und D ihy­drokawain. Arch. intern. Pharmacodyn.148(1-2) :97-110.

PAlLER, M., G. SCHADEN, and R. HANSEL.1965. Massenspektren von a-Pyronen vomTypus der Kawa-Lactone. Monatsh. Chem.96(6) :1842-1849.

TITCOMB, M. 1948. Kava in Hawaii. J. Polynes.Soc. 57(2) :105-20l.

VAN VEEN, A. G. 1938 . Over de bedwel­mende stof uit de kawa-kawa of wati-plant( Piper methystiaon] , Geneesk. T ijdschr.Ned.-Ind . 78:1941-1953.

W ERNY, F., and R. HANSEL. 1963. Die Hy­drierung von 6-Styryl-a-Pyronen zu Wirk­stoffen vom Typus der Kawa-Lactane (ausPiper methystimm) . Naturwissenschaften50(9) :355.