peptide hormone analogues and novel clinical applications

PEPTIDE HORMONE ANALOGUES AND NOVEL CLINICAL APPLICATIONS

ALBERTO ANGELI

Istituto di Medicina lnterna, Cattedra di Patologia Speciale Medica e Metodologia Clinica D, Universitgz di Torino.

In the past decade there have been major advances in peptide physiology, which have raised new possibilities to the exogenous manipulation of the endocrine milieu. The background is certainly related to the excitement over several molecules that act as hormones and neuromodulators and to the delineation of complex precursor molecules such as pro-opiomelanocortin (POMC). It is now established that, in the anterior pituitary, POMC is processed predominantly to a '16K' fragment, ACTH and lipotrophin (LPH); further

~ rocessing to a mixture of peptide fragments that include st-MSH and several -endorphin related peptides occurs in the anterior and intermediate lobe cells

as well :~. According to SC~WVZER s~ the precursor protein mediate the pleiotropic action of one single gene that codes for a number of different hormonal sequences on the same protein. Moreover, due to the molecular flexibility and the organization of adjacent aminoacid sequences, peptide hormones have another type of pleiotropic information. Functionally different, structurally independent or slightly overlapping sequences may be discerned that refer, on the one hand, to the active site or message for a given receptor and, on the other hand, to auxiliary regions that comprise potentiating, addressing, and protecting subunits. This form of organization, called sychnologic (from the Greek terms sychnos = compressed, condensed, and logos -- word) accounts for different yet complementary biological actions that, in the case of ACTH, may all serve to meet emergencies of the daily activity. In this light, it is not surprising that POMC processing and ACTH secretion be organized to vary rapidly under a variety of stimulatory conditions. Complex neuroendocrine events modulate another fundamental feature of this secretion, i.e. the rhythmi- city which is arranged along multifrequency scales, the circadian one being prominent in adult humans.

Ke~-words: ACTH: Chrononeuroendocrinob)gy: Clinical application: Gn-RH; Peptide hormone analogues.

La Ricerca Clin. Lab. 1.1, 123, 1984.

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The circadian (24-h periodic) oscillation of plasma ACTH has been well characterized. Studies in which blood samples were drawn as often as 20 to 30 rain allowed the demonstration that ACTH is released in intermittent secretory bursts interspersed with intervals of quiescence ',s". Investigation is yet needed to ascertain whether ultradian (frequency-computable and thus predictable) rhythms account for this pattern, and 'episodes' are an expression of basic periodicities, possibly intermodulating with other spectral components of endogenous or exogenous control. In any event, the episodic secretion does not obscure the circadian program, which normally emerges as a clustering of intense secretory episodes during the early morning hours and is easily evidenced with methods of time series analysis. The circadian patterns of plasma glucocorticoid and ~-LPH/~-endorphin concentrations show close correlations with those of ACTH 2737,3:. There is contradictory evidence (in species with an intermediate lobe) as to the presence of synchronism also with the release of ct-MSH, which has been suggested to occur with a circadian pattern s~,6~ The recent definition and synthesis of a 4 1-aminoacid corticotropin-releasing factor (CRF) from ovine hypothalamus, that has full activity in humans and appears to be a major factor mediating the release of POMC-related peptidesS% will undoubtedly permit more critical assessment of the role of CRF in the control of rhythmicities of these peptides. Earlier reports of a circadian periodicity of bioassayable corticotropin-releasing activity in rat hypothalamus:4 have already been revisited with the ability to measure CRF concentrations35 The availability of the synthetic releasing factor, moreover, prompts chronopharmacological investigation that will throw light on the neurotransmitter regulation of CRF release, hence on the relationships between the rhythmic processing of POMC at the pituitary level and the putative central nervous pacemakers and pace- resetters.

Present knowledge suggests that the circadian secretion of any endocrine structure is basically an expression of the genetic chrono-organization of the hormone-producing cells. In other words, a rhythmic release into the blood- stream may occur independently from a rhythmic stimulation. On the other hand, the activity of the so-called pituitary-adrenal axis is to a great extent dependent on effective hierarchical information, that needs proper reception at subsequent levels. The parallelism between the plasma profiles of POMC- related hormones and cortisol lends support to the view that peptides (CRF? ACTH? Specific sequences?) modulate physiologically the adrenocortical rhythm by conveying both endogenous (genetic) and environmental control along a well defined temporal scale. Accordingly, the acrophase of the human glucocorticoid secretion in the circadian domain is roughly coincidental with the initiation of the diurnal activity. The role of peptide information deserves most attention if one considers that the adrenocortical cycle constitutes an endocrine entity in its own right (a signal to be received by target cells), preparatory for daily activity and not merely a response to changes in the environ- ment or to vicissitudes of life:'.

The same concept applies to other fundamental endocrine activities. Gona- dal steroid secretion is dependent on pituitary gonadotropins which in turn receive complex messages from their hypothalamic releasing hormone (Gn-RH). Chrono-modulation of Gn-RH action is a very important area of research. The recognition of the multifrequency spectrum of rhythms, that

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physiologically accounts for gonadotropin release and germ cell maturation, has already opened new avenues to the diagnosis and therapy of hypogonadotropic hypogonadism 3',34. Chemical synthesis of analogues with agonist or antagonist activity is the logical consequence of any progress in the field of biologically active peptides. Here below some more recent aspects of clinical interest will be discussed, with special regard to ACTH- and Gn-RH-related peptides.

Peptide hormone agonists: a growing family with different biological targets Within the last few years there has been a remarkable change in our

understanding of the process of chemical signalling in the central and peripheral nervous system. Ten years ago less than 10 monoamine and aminoacid neurotransmitter candidates were known, but to these must now be added 30 or more peptides, each with a potential messenger function 29. Several recent reviews provide detailed information3.1'.~2.29.~. The concept that peptides derived from POMC act not only as hormones for peripheral targets, but also as modulators of neural processes in the brain is now affirmed. ACTH and the closely related ct-MSH apparently affect the level of arousal, alertness and attention, the processing of sensory input, consolidation and retrieval of memory, all aspects thought to be essential for coping with situations of emergency and for adaptation to environmental changes '9. The effects on central nervous activities appear to be independent, at least to a significant extent, from the peripheral steroidogenetic action. Thus, ACTH is an example of a peptide hormone that influences both somatic and psychic phenomena functioning as a chemical integrator between cognition and adaptation to changing external conditions.

It was speculated that ACTH and/or its peptide fragments could reach their brain targets through transportation by reverse flow via the pituitary portal vessels or by way of the cerebrospinal fluid 2". More recently, the passage across the blood-brain barrier of diverse peptide molecules has been convincingly ascertained 4~ Thus, one could postulate that ACTH is released by the anterior pituitary into the general circulation, exerts its stimulatory action at the adrenal level, is processed and cleaved to peptide fragments that are taken up into the brain where they exert further effects in order to increase alertness and awareness. Interestingly, one important function of the blood-brain barrier is the rapid enzymatic cleavage of peptides, due to the high aminopeptidase activity of brain capillaries ~7.

A complex picture emerges from the interactions of direct and indirect effects of ACTH-related peptides on the brain, while considering that glucocorticoids themselves profoundly affect behavior and mood. Psycho-modulating effects appear, in part, synergistic and mutually supporting, in part, however, mutually opposing 18. The extensive search by De Wied and associates for an active core in the ACTH molecule which is responsible for the behavioral activity has provided novel insights into this rapidly developing area 3.H,~2,'9. It was found that essential information was not confined to a single fragment, but was present in different loci of the ACTH molecule and of the other POMC-related peptides as well, in accord with the general sychnologic organization. The aminoacid sequence ACTH~.., has received particular attention in the light of its behavioral effective,hess and of" the absence of any effect at the

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adrenal level. A large number of analogues has been synthesized with the aim of improving specific effects through the introduction of some modifications in the primary sequence. Substitution, for instance, of a D-lysine residue for arginine in position 8, combined with two minor modifications at the C-and N-terminals, resulted in an analogue named Org 2766, i.e. H-Met(O2)-Glu-His- Phe-D-Lys-Phe-OH, which showed a thousandfold increase of potency in one test of adaptive behavioral activity, but which had lost all activity in another test and in the opiate receptor assay 19. On the other hand, exchange of the phenylalanine residue in position 7 by its optical antipode gave the analogue named Org OI 64, i.e. H-Met-Glu-His-D-Phe-Arg-Trp-Gly-OH, which showed consistent affinity for the opiate receptor but a completely different pattern of behavioral effects in comparison to Org 2766. The elongation of this latter analogue with the sequence [D-lys"JACTH~0_~6-NH2 further increased the potency by at least a factor 1,000. Concurrent introduction of other modifications yielded an analogue named Org 5042 which appeared under particular experimental conditions up to a million times more active in rats than the reference peptide ACTH~,~0~9.

From these studies on the structure/activity relationships it was suggested that the stereochemical conformation of the peptide sequences represents one critical variable at the receptor site and that spatial interaction may lead to mutually interfering effects on the same brain processes by closely related fragments from the same precursor molecule. Heterogeneity of receptors is another important aspect. Analogues which differ in the degree of affinity for the specific binding sites may conceivably privilege one (beneficial) or another (adverse) biological effect. This point raises some questions as to the applicability to humans of the behaviorally active peptides related to the ACTH~.,0 sequence. Differences in hormone/ receptor interactions have been repeatedly documented to occur among mammalian species and numerous effects of peptide and steroid hormones on central nervous activities appear specific for the rodent brain and do not warrant extrapolation to primates. Notwithstand- ing these limitations, recent reports have pointed to the effectiveness of the analogue Org 2766 in enhancing attention, vigilance and motivation also in humans ~7.

Another line of ACTH-related analogues takes into consideration also the corticotropic sequence and addresses new molecules to both somatic and psychic effects in order to gain clinical applicability by means of a more complete action. The rationale is related, on the one hand, to the sychnologic organization of longer aminoacid sequences and, on the other hand, to possible complementary effects of the stimulated glucocorticoids and of peptide fragments at diverse target levels, central nervous system among others.

Attention has been focused upon the N-terminal sequence of 18 aminoacids which was demonstrated to retain full biological activity on the adrenal cortex provided that the carboxylic C-terminal group be protected as amide against the enzymatic degradation: H-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- Val-Gly-Lys-Lys-Arg-Arg-NH> The most interesting molecule, among the great number of analogues which were derived from the above sequence, was built with the substitution of a ~-alanine residue for serine in position 1, of a lysine residue for arginine in position 17, and of a basic amide lot the C-terminal

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arginin-amide. This heptadecapeptide analogue, named Hoe 433 (alsactide) or Synchrodyn | 1-17, i.e. ~-Ala-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro- Val-Gly-Lys-Lys-Lys-NH(CH~)~-NH2 was demonstrated to exert a very potent corticotropic action when studied in comparison with natural ACTH preparations or synthetic fragments of longer chain ~.ss. Binding of the analogue to the adrenal cells or to frog skin preparations (melanotropic activity) lasted longer than for natural ACTH or o:-MSH; it was suggested, therefore, that progressive chain shortening and substitution of the N- and C-terminal aminoacid residues resulted in enhanced biological activity also as a consequence of conformational changes that favor binding to receptors ~9. The analogue had positive inotropic activity in dogs and cats, an effect shared by natural ACTH and wMSH32; these observations, taken together with the evidence for myocardial ACTH receptors 61, support the view that the heptadecapeptide effectively operates on adrenal and extra-adrenal targets as well. Extensive applications to humans has then confirmed both the corticotropic potency and the wide flexibility for the clinical use of this analogue =,'4,~.

This volume provides evidence that time-qualified administration of the analogue is valuable in several clinical conditions. The dose used in almost all studies (1 00 btg i.m. just before the morning peak of endogenous cortisol levels) was demonstrated to be highly effective in stimulating adrenocortical steroidogenesis. Injections for 15 consecutive days were associated in some cases with a marked enhancement of plasma steroid concentrations and with a subse quent loss of sensitivity to endogenous stimulation. Noteworthy was the presence in any case of a high-amplitude circadian oscillation. A number of patients, especially those with advanced cancer and /or malnutrition, exper- ienced melanoderma, which did disappear after discontinuance of the treat- ment. This observation is of interest in the light of the sychnologic organization as it seems logical to think that the melanotropic sequence of the molecule is more 'uncovered', hence more effective than in other corticotropic preparations. Therefore, the melanotropic effect could be viewed not as a side effect but as a marker of the biological potency and be utilized to monitoring dose/effectiveness in diverse disease conditions.

Generally speaking, either ACTH-related agonists confined to the 4-10 sequence or those addressing also to the corticotropic core have indicated that F-bend-like, loop-like or helix-like structures are determinants of the spatial interaction with receptors, hence of the biological activity. Rapid turns often occur in the conformational model of even small peptides and have become increasingly important for the design of peptide hormone analogues. From structurally elucidated peptides, the assumption can be made that only a few aminoacids promote the formation of conformational bends, glycine being most frequently involved '6. Introduction of a D-aminoacid instead of glycine leads in most instances to increased and prolonged biological activity, particu- larly when the side chain ofa D-aminoacid participates to the spatial interaction with the receptor 33. This assumption has received ample experimental support from predictive studies aimed to evaluate the biological potency of 'program- med' peptides and, most recently, to examine the binding characteristics of receptors and the subsequent processing of receptor-peptide complexes ~*.

In the early 80's interest has been raising about the superactive synthetic agonists of the hypothalamic gonadotropin-releasing hormone (LH-RH;

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gonadorelin), a decapeptide with the sequence Pglu-His-Trp-Ser-Tyr-Gly-Leu- Arg- Pro-Gly-NH>Conformational analysis of the molecule was compatible with the presence of a ~-bend-like structure comprising the sequence Tyr-Gly-Leu- Arg 36. Pertinently, substitution of a D-aminoacid residue for glycine caused a dramatic increase in the biological activity, depending on the shape of the side chain*6. Besides conformational changes, these analogues have an important protection against enzymatic degradation that mainly starts at the bond between 5-tyrosine and 6-glycine. A further step in the chemical engineering of superactive agonists of LH-RH was achieved when Gly-NH2 in position 10 was substituted by ethylamide. Again, the most logical explanation for the manifold increase of potency is that of a cooperative effect at the receptor level in addition to improved stability against enzymes. The result of this sophisticated work of peptide synthesis, the nonapeptide Hoe 766 or buserelin, i.e. Pyp-His- Trp-Ser-Tyr-D-Ser-(TBU)-Leu-Arg-Pro-NH-CH2-CH3 is now under extensive clinical investigation for the control of reproductive function and for the therapy of several disease conditions including hormone dependent tumors. A large body of research has been concentrated in exploring the mechanisms whereby superactive LH-RH-related analogues interfere with the pituitary-gonadal function, after the demonstration that native LH-RH exerts its physiological function by high-frequency ultradian ('pulsatile') stimulation ofgonadotropin release whereas continuous exposure results in a block of the release and in a reduc- tion of pituitary LH/FSH content. Most probably, desensitization and /o r down- regulation of LH-RH receptors account for the paradoxical effects observable after supraphysiological or continuous hormone exposure% in that pituitary ceils apparently do not require internalization of LH-RH-receptor complexes for biological activation'".

In turn, the physiological rhythmic release of LH from the pituitary main- tains proper conditions of gonadotropin binding to receptors at the gonadal cell level, at least in adult animals and humans 4'. Therefore, LH-RH synthetic agonists with enhanced potency and duration of action possibly lead to desynchronization of the already mentioned complex rhythmic events that underlie the hierarchical organization of the pituitary-gonadal axis and its normal function. The final consequence is a temporary block of gonadal activation despite impressive agonistic activity with respect to the endogenous stimulatory hypothalamic hormone. New findings have added complexity to the issue. Specific receptors for LH-RH have been localized on the Leydig cells of the rat testis and in ovarian preparationsS.% and it has been suggested that LH-RH agonists act directly at the gonadal level to affect steroidogenesis. Data are available which are consistent with the ability of LH-RH agonists to inhibit ovarian and testicular steroidogenesis in vitro 2s,45, This effect requires experimental conditions (dose and exposure time, among others) that differ from those applicable when one wishes to explore desensitization at the pituitary leveP 3. While the mechanisms of the direct inhibition of gonadal steroidogenesis by LH-RH agonist molecules remain unclear, it seems reasonable to look at multiplicity of receptors for LH-RH in different organs. Receptor multiplicity has been observed for other neuropeptides ~'~ and it has been shown that the ability of exogenous agents to occupy these receptors may be profoundly different from one organ to another'". In this light, superactive LH-RH agonists

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could be viewed as a family of pharmacological agents that affect reproductive function through a number of mechanisms that are influenced, at least to a certain extent, by the target organ responsiveness. As in the case of ACTH- related analogues, and other peptides as well, peculiar aminoacid residues and the relevant conformational turns may present more critical keys for interaction with a given receptor, whereas they may be of secondary importance for another. The use of experimental models where endogenous gonadotropin release is neutralized (hypophysectomy, anti-LH serum) will possibly ameliorate our understanding upon the gonadal effects of LH-RH-related analogues and provide data for future synthesis of more specific molecules.

Dose and timing as critical variables for clinical application

Physiologists and clinicians are now increasingly aware that the neurohor- monal control of the human body living a conventional existence o r adapting to environmental changes and injuries is related to a complex program of rhythmic messages. This awareness also depends on methodologically critical advances. In fact, the availability of a set of instruments and methods for data collection, transfer, storage and analysis allows the multifrequency spectrum of rhythms to be meaningfully yet cost-effectively identified and assessed by inferential statistical means 6. By the use of such methods, often applicable with pocket calculators, several pitfalls of misinterpreting data obtained on the basis of single samples at fixed times can be avoided'.

A central issue in chrononeuroendocrinology is related to the pathogenetic role of time structure alteration in illness. When appropriately evaluated in terms of changed values of cosine curve parameters (mesor, amplitude and acrophase), available data are consistent with the appearance of abnormal characteristics of several endocrine rhythmicities not only in patients with overt disease but even in people at risk. Much remains to be learned about alterations of the temporal ordering of the hormonal information and the mechanisms whereby such alterations may play a role in the development and/or clinical course of several disease conditions. At least in some circumstances (and for some frequency domains) one could postulate that desynchronization is a marker of the disease status (and therefore a reliable indicator and an aid to diagnosis) rather than a causal factor, in that it approaches normal as the disorder is treated. There is supporting evidence, however, that under other circumstances spectral changes in the endocrine rhythms precede more conventional signs of the illness; thus, the chronobiological approach raises the possibility that effective preventive measures could be taken:".

Broadly speaking, the major body of knowledge about the applicability of rhythm desynchronization to clinical problems pertains to the hypothalamic- pituitary function and intermodulating hormones, primarily adrenal and gonadal steroids. The pineal gland is also involved because it admittedly functions as a coupling device between oscillators located in the hypothalamus and elsewhere. Melatonin, as well as other pineal products, may play an important role in determining the temporal organization of various peptidergic neurons as well as affecting target tissue sensitivity. For instance, it has been demonstrated that a corticotropic effect upon the adrenal steroidogenesis is atten- uated, amplified or left unaffected by the pineal depending on the circadian stage%

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Hormones and synthetic agonists which conceivably interfere with the temporal ordering of the endogenous signals have to be applied in medicine taking into account the fact that such exogenous agents interact with the genetic temporal features of the organism in a broadly different way in relation to both timing and dose. Three aspects deserve major clinical interest. First, a noteworthy gain in the therapeutic index can be achieved by proper timing as established by about 10 years with unquestionable success for glucocorticoids 8. Second, the chronobiological approach offers the chance for using old and new molecules with the purpose of correcting any rhythmic alteration. which may be a determinant of the disease status. Third, a novel application is that of the so-called chronization, i.e. the presetting, by the administration of a particular agent, of the tolerance of a substance (for example, an anti- cancer drug) comparable to that encountered at the peak of the circadian cycle in susceptibility or tolerance = . It is noteworthy that this goal of presetting tolerance has been achieved by giving the heptadecapeptide analogue Synchro- dyn | 24 h prior to adriamycin in mice ~~ It is yet unclear whether the chronizing effect depends solely on the adrenal stimulation which, in all species examined, shows a changing pattern of response from one stage to another of the circadian cycle ,.::.:3,,.

In most papers included in the present volume, chronization by ACTH 1-17 was attempted with the use of a relatively high dose (100 p.g i.m.). It was demonstrated that very small doses of the peptide were effective on the human adrenal gland in stimulating selectively glucocorticoid versus mineralocorticoid release and in eticiting a relatively short-lasting plasma cortisol wave 2. On this basis, the use of lower doses could be more advisable for resetting or presetting of the circadian system, especially if one looks at those rhythmicities that are more dependent on the glucocorticoid modulation. Pertinently, Dammacco et al. draw attention in their paper on the importance of the relationship between the endocrine information and the rhythmic organization of some prominent immune functions.

Regardless of which biochemical processes are involved, including the pineal influences by the so-called feed-sideward mechanism% the circadian changes in the adrenal responsiveness to exogenous ACTH, yet present in transplanted and enucleated rat glands~7, support the view that there exists a genetic program to amplify and reset the corticosteroidogenesis relative to ACTH inputs. This program not only yields release of different amounts of steroid hormones after administering the same stimulation at different circadian stages but also intrudes upon the quality of the response, i.e. on the effects upon glucocorticoid versus mineralocorticoid steroidogenetic line 23.". Mor- eover, the adrenal glands are prepared to respond in a different way to different concentrations of adrenocorticotropic molecules and possibly to different modes of exposure (stimulatory pulses or continuous infusion). It has been demonstrated, for example, that acute injection of increasing doses of the analogue ACTH 1-1 7 is a useful tool in diagnostics to investigate separately the responsiveness of cortisol and aldosterone secretion in humans 2. Thus, manipulating dose and timing of the administered analogue could provide information about specific pathogenetic mechanisms and /or subtle alterations of the adrenal function, that are not evidenced with any conventional approach based on supramaximal ACTH stimulation. In this sense, the use of a synthetic

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peptide presenting a wide range of programmable effects appears essential for a better medicine.

There is no doubt that most actions of LH-RH related peptides are influenced by dosing and chronobiological application. Recent reviews provide a large body of evidence both in experimental animals and in humans ~8.s3'ss. Divergent effects depending on the experimental conditions have been observed for both pituitary and gonadal events elicited by exposure to superac- tire agonists. This is not surprising if one considers that the action of the gonadal steroids and coordinating hormones, primarily gonadotropins and prolactin, comprises a number of cellular and molecular events that display rhythmic changes along several frequencies. The responsiveness to endogenous and exogenous signals is conceivably different at different stages of such bioperiodicities. As in the case of ACTH 1-17, the chronoendocrinological approach is upgrading the heretofore underestimated role of timing in the development of new strategies for clinical application.

The efficacy of the so-called low-dose pulsatile LH-RH therapy in the management of hypogonadotropic hypogonadism and of some forms of inferti- lity may be viewed as another piece of evidence for this assumption. The raising knowledge about this particular application of hormonally active peptides has been dependent on the creation of reliable automatic devices for releasing pulses of the molecule at programmable frequency. Now small computerized portable pumps are available and during the last few years several reports have confirmed the successful induction of follicular maturation and ovulation or of testosterone production and spermatogenesis in gonadotropin-deficient patients ~9,52. It is apparent, therefore, that chrononeuroendocrinology and bio- technology are mutually supporting in the endeavor to provide new and very promising approaches to peptide application.

Concluding remarks and perspectives

Peptide hormones are manufactured and stored in specialized endocrine cells and then released to reach specific targets. In most cases the hormonal message is known to be conveyed to the target cell through interaction with a specific cell surface receptor; hormone degradation, often mediated by receptor binding and internalization, is a further common feature. We clearly need to better define the molecular conformation of these peptides during their complex life cycle if we wish to understand the biological activities and to have a more reliable rationale both for chemical synthesis and for clinical application of the analogues. Many POMC-related peptides, for instance, show great conformational flexibility in aqueous solutions; the existence of a pre- ferred structure may depend not only on changes in the solvent milieu but also on whether the molecule is charged or not and on the concentration ". This may be important for differential binding to multiple receptor sites in the case of any exogenously administered analogue. Besides dose and timing, another critical variable could be sought in the degree of molecular flexibility.

Identification of receptor-bound 'conformers' awaits intensive investigation; in this respect, compared to the native more flexible molecule, a more rigid synthetic analogue appears to be advantageous in that there is a smaller loss of entropy on formation of the receptor-hormone complex ~. An additional perspective comes from better definition of the molecular aspects of peptide

13t


h o r m o n e r e c o g n i t i o n : t h a t o f s y n t h e s i z i n g n e w g e n e r a t i o n s o f a n a l o g u e s w h i c h wi l l e x p l o r e d e e p e r a few o r e v e n o n e s i n g l e b i o l o g i c a l r e s p o n s e . A t t h e p r e s e n t s t a te o f k n o w l e d g e , h o w e v e r , o n l y a g e n e r a I v i e w is b e g i n n i n g to e m e r g e a n d t h o u g h s i g n i f i c a n t p r o g r e s s h a s b e e n m a d e r e c e n t l y , s e v e r a l w a y s o f o p t i m i z i n g the a l r e a d y s o p h i s t i c a t e d a p p l i c a t i o n o f p e p t i d e h o r m o n e a g o n i s t s i n m e d i c i n e r e m a i n o p e n for f u t u r e r e s e a r c h .

SUMMARY

Clinical application ofpeptide hormone analogues is rapidly expanding. Peculiar aminoacid residues, conforma.tional turns and the degree of molecular flexibility may represent critical keys for differential interaction with the receptor sites, hence for specific biological effects. Broadly different biological responses may be elicited as a function of dose and timing of administration. The clinical use of the heptadecapeptide analogue ACTH 1-17 (Synchrodyn | 1-17) has provided new diagnostic information about subtle alterations of the adrenal function and has been valuable to presetting the rhythmic ordering of several functions, especially of those which are more dependent on the glucocorticoid modulation. In this sense, the use of a synthetic hormone analogue presenting a wide range of programmable effects appears essential for a better medicine. A large body of evidence indicates that the same concept applies to most actions of the gonadotropin-releasing hormone (LH-RH) related analogues. The availability ofsmalt computerized instruments for data collection and analysis of the endogenous rhytmicities, on the one hand, and for programmable administration of the analogues, on the other hand, is already providing new approaches to heretofore unsuccessful therapies.

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ALBERTO ANCELI

Patologia Medica D Ospedale San Vito, Strada San Vito 34 10133 Torino, Italy

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peptide hormone analogues and novel clinical applications

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