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Muscarinic Receptors pp 343–374Cite as

Muscarinic Agonists and Antagonists: Effects on Gastrointestinal Function

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 208))

Abstract

Muscarinic agonists and antagonists are used to treat a handful of gastrointestinal (GI) conditions associated with impaired salivary secretion or altered motility of GI smooth muscle. With regard to exocrine secretion, the major muscarinic receptor expressed in salivary, gastric, and pancreatic glands is the M3 with a small contribution of the M1 receptor. In GI smooth muscle, the major muscarinic receptors expressed are the M2 and M3 with the M2 outnumbering the M3 by a ratio of at least four to one. The antagonism of both smooth muscle contraction and exocrine secretion is usually consistent with an M3 receptor mechanism despite the major presence of the M2 receptor in smooth muscle. These results are consistent with the conditional role of the M2 receptor in smooth muscle. That is, the contractile role of the M2 receptor depends on that of the M3 so that antagonism of the M3 receptor eliminates the response of the M2. The physiological roles of muscarinic receptors in the GI tract are consistent with their known signaling mechanisms. Some so-called tissue-selective M3 antagonists may owe their selectivity to a highly potent interaction with a nonmuscarinic receptor target.

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Abbreviations

A23187:

5-(Methylamino)-2-({(2R,3R,6S,8S,9R,11R)-3,9,11-trimethyl-8-[(1S)-1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl}methyl)-1,3-benzoxazole-4-carboxylic acid

AF-DX 116:

11-[[2-[(Diethylamino)methyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one

AQ-RA 741:

11-[[4-[4-(Diethylamino)butyl]-1-piperidinyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one

4-DAMP:

N,N-dimethyl-4-piperidinyl diphenlyacetate

4-DAMP mustard:

N-(2-chloroethyl)-4-piperidinyl diphenylacetate

GI:

Gastrointestinal

HHSiD:

Hexahydro-sila-difenidol

[3H]NMS:

[3H]N-methylscopolamine

I cat :

Nonselective cation conductance

K B :

Dissociation constant of the antagonist

KO:

Knockout

pK B :

Negative log dissociation constant

pK D :

Log binding affinity constant

p-F-HHSiD:

para-Fluoro-hexahydro-sila-difenidol

TRP:

Transient receptor potential

KCa :

Ca2+-activated potassium channel

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of California, Irvine, CA, 92697-4625, USA

    Frederick J. Ehlert, Kirk J. Pak & Michael T. Griffin

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  1. Frederick J. Ehlert
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  2. Kirk J. Pak
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  3. Michael T. Griffin
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Correspondence to Frederick J. Ehlert .

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Editors and Affiliations

  1. UHN67, Department of Pulmonary and Critical Ca, Oregon Health & Science University, SW Sam Jackson Park Road 3181, Portland, 97239, Oregon, USA

    Allison D. Fryer

  2. , Department of Pharmacology, Monash Institute of Pharmaceutical Scien, Royal Parade 381, Parkville, 3052, Victoria, Australia

    Arthur Christopoulos

  3. , Department of Pharmacology, University of Washington, Seattle, 98195-7750, Washington, USA

    Neil M. Nathanson

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Ehlert, F.J., Pak, K.J., Griffin, M.T. (2012). Muscarinic Agonists and Antagonists: Effects on Gastrointestinal Function. In: Fryer, A., Christopoulos, A., Nathanson, N. (eds) Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9_15

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