Muscarinic Agonists &

Antagonists

Brian J. Piper, Ph.D., M.S.

Objectives

• Similarities & differences in muscarinic receptors

• Agonists – Synthetic: methacholine– Natural: pilocarpine

• Antagonists– atropine– scopalomine

*

* Acetylcholine & muscarinic receptors for sweat glands

Howland & Mycek (2006). Lippincott’s Illustrated Reviews: Pharmacology, p. 56.

Acetylcholine

• This neurotransmitter does not make a good drug because:– Limited penetration (quaternary ammonium) of

the Blood Brain Barrier

– Peripheral enzymes (butyrylcholinesterase) degrade it quickly

Muscarinic Receptors

• Metabotropic– M1, M3 & M5 via Gq

– M2 & M4 via Gi

• Orthosteric binding site (ACh) highly conserved, allosteric binding site moderately conserved

• Non-selectivity within M1-M5 • Co-expression

Amanita muscaria

12 Cranial Nerves

• On Old Olympic Towering Tops A Finn And German Viewed Some Hops

• Once One Openly Told Tourists About FightingVampires Gobling Various Antelope Herds

• Oh Once One Takes The Anatomy Final Very Good Vacations Are Heavenly

http://en.wikipedia.org/wiki/List_of_mnemonics_for_the_cranial_nerves

Overall Receptor Distribution

• Cranial Nerve– III: oculomotor– VII: facial– IX: glossopharyngeal– X: vagus

http://flipper.diff.org/app/items/info/4260

Immunocytochemistry (ICC)

• Uses immune system to generate antibodies• Antibodies are applied to tissue to localize

protein (receptor, enzyme)

M1 to M4 ICC Localization for I3

M1 M2

M3 M4

Levey (1993). Life Sciences, 52, 441-448.

Neural Localization

Stahl, S. (2008). Essential Psychopharmacology, p. 916.

Tissue Distribution

Receptor OrgansM1 salivary glands, enteric nervesM2 heart, smooth muscleM3 smooth muscle, salivary glandsM4 brain (diffuse), lungM5 brain (substantia nigra), eye

Andersson, K. E. http://www.medscape.org/viewarticle/487222

Muscarinic Agonists

Origin NicotinicEffect

BBB Permeability

Uses

Methacholine synthetic low low challenge for asthma

Carbachol synthetic high low miosisglaucoma

Muscarine natural no low researchhallucinogin

Pilocarpine natural no high xerostomia

Brown & Laiken (2011). In Pharmacological Basis of Therapeutics, p. 219-237.

Bethanechol

• Short-acting muscarinic agonist

• Used to treat non-obstructive urinary retention

Atropa belladona

• Atropos: Greek god of life• Belladona: dilation of pupils• Contains nonselective muscarinic

antagonists atropine & scopolamine• Overdose = dry mouth, confusion,

seizures

1707 - 1778

Carl Linnaeus

Atropine

Rang et al. (2007). Pharmacology. p. 145.

1875 - 1968

Pharmacological Actions of Atropine

• Heart: decrease (low-dose)/increase (high-dose)• Lungs: inhibit histamine induced

bronchoconstriction• Eyes: mydriasis but long-lasting • Salivation: reduced• Sweating: reduced

Relative Physiological Effects

Katzung et al. (2009). Basic & Clinical Pharmacology. p. 120.

Red as a beet (heat compensation)Dry as a bone (decreased salivation)Blind as a bat (mydriasis)Hot as firestone (decreased sweating)Mad as a hatter (CNS/hallucinations)

Scopolamine

• Crosses BBB• Used prophylactically• Adverse Effects: dry

mouth, drowsiness

Silly but accurate (1 min): http://www.youtube.com/watch?v=h88Vg3PrKIs&feature=BFa&list=LPq4H22JxqqS4

Datura stramonium• Plant found in North America, Europe, Asia• Jimsom weed, witch’s brew, thornapple• Plant contains atropine & scopolamine• Historical asthma treatment & used to

facilitate bone setting

Miraldi et al. (2001). Fitoterapia, 72, 644-648.

Are seeds special?

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Homeopathy• Atropa belladona used for centuries including as a tincture “like

treats like”• 30C (centesimal) dilution involves 30, ten-fold dilutions• Double-blind randomization to Placebo for one-week then (N =

253/206) double-blind randomization to 30C or placebo for more 2 weeks

• Daily questionnaire of belladona symptoms (My pupils are unusually dilated, especially when I feel hot)

• Independent verification that 30C versus placebo blinding was successful.

Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568. 1755 - 1843

Samuel Hahnemann, MD

Nadu, India

Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.

“Deadly nightshade”

Brien et al. (2003). British Journal of Clinical Pharmacology, 56, 562-568.

Conclusion: Pro: no side effectCon: not harmless

Atropine Induced Coma Therapy

• Physical withdrawal is unpleasant• Coma Therapy has a long-history (1930s) but

limited data on safety & efficacy • Drug addiction involves both physical &

psychological components

1.5 min: http://www.youtube.com/watch?v=r7HSokv8A5M&feature=player_detailpage

Forrer, G. (1956). J Nervous Mental Disease, 124(3), 256-259.

Summary

• Muscarinic agonists used to treat urinary retention & xerostomia. Muscarinic antagonists useful for OAB, COPD, and in ophthalmology with local application.

• Lack of selectivity results in difficulty with patient adherence.

Future: Selective Muscarinic Allosteric Modulators?

Future: Selective Muscarinic Allosteric Modulators?

PQCA: M1 positive allosteric modulator; donepezil: acetylcholinesterase inhibitor

Uslaner et al. (in press-2012). Psychopharmacology.

Goodwin Terminology (Refresher)orthosteric: site where the ligand binds to a receptor or enzymeallosteric: the other site (non-active site)positive allosteric modulation: binding of ligand to allosteric site increases binding between substrate molecules & other binding sitenegative allosteric modulation: binding of ligand to allosteric site decreases binding between substrate molecule & other binding sitedystonia: involuntary muscle contractions that cause slow repetitive movements or abnormal posturescycloplegia: inability to focus eye for near visiondiaphoresis: excessive sweatingdiverticulitis: formation of small bulging pouches in the lining of intestine that become inflamedmiosis (myosis): constriction of the pupil of eyemydriasis: dilation of pupil of eyesialagogue: any drug or agent that can stimulate the flow of salivaxerostomia: dry mouthsyncope: fainting