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β 3 ‐adrenoceptors and intestinal motility
Author(s) -
Manara L.,
Croci T.,
Landi M.
Publication year - 1995
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1995.tb00507.x
Subject(s) - receptor , beta (programming language) , motility , adrenergic receptor , in vivo , beta 3 adrenergic receptor , biology , pharmacology , agonist , beta 1 adrenergic receptor , endocrinology , medicine , chemistry , biochemistry , microbiology and biotechnology , genetics , computer science , programming language
Summary— Early substantial evidence of the low susceptibility to β‐adrenoceptor antagonists of non α‐adrenergic responses reducing gut motility and tone was reluctantly accepted as indicating a third β‐receptor subtype different from the β 1 and β 2 . This applied likewise to lipolysis until new selective “lipolytic” β‐agonists poorly effective at established β‐receptors were introduced. Shortly afterwards these “lipolytic” as well as certain newer and even more selective β‐adrenoceptor agonists were shown to be potent inhibitors of intestinal motility. The latter are the “gut‐specific” phenylethanolaminotetralins whose availability as pure isomers attested to the stringent stereochemical requirements for selectivity at non‐β 1 , non‐β 2 β‐adrenoceptors. Acceptance of the functionally based concept of a β 3 ‐adrenoceptor was boosted on structural grounds by molecular biology studies. Sequence analysis indicated the existence in humans and rodents of genes coding for a third subtype of β‐receptor that, when expressed in transfected heterologous cells, had a pharmacological profile distinct from the previously established subtypes. Finally, aryloxypropanolaminotetralins have been prepared as the first selective antagonists of β 3 ‐adrenoceptors, thus providing unambiguous conclusive evidence of the distinctive functional features of those abundant in the rat colon. The therapeutic potential in gastroenterology of the newer compounds targetable on the β 3 ‐adrenoceptor is suggested by their potent intestinal action in vivo in animal models without any of the cardiovascular or other unwanted effects of conventional β 3 ‐adrenoceptor agonists and antagonists, and by the clinically confirmed importance of β‐adrenergic control of motor function throughout the alimentary canal. However, open questions include the incidence of species‐related differences in β 3 ‐adrenoceptors, and as yet there are no data on gastrointestinal functions in humans under the influence of drugs designed to act selectively at these receptors.