Beta 3-adrenoceptors and intestinal motility.
Early substantial evidence of the low susceptibility to beta-adrenoceptor antagonists of non alpha-adrenergic responses reducing gut motility and tone was reluctantly accepted as indicating a third beta-receptor subtype different from the beta 1 and beta 2. This applied likewise to lipolysis until new selective "lipolytic" beta-agonists poorly effective at established beta-receptors were introduced. Shortly afterwards these "lipolytic" as well as certain newer and even more selective beta-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-beta 1, non-beta 2 beta-adrenoceptors. Acceptance of the functionally based concept of a beta 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 beta-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 beta 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 beta 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 beta-adrenoceptor agonists and antagonists, and by the clinically confirmed importance of beta-adrenergic control of motor function throughout the alimentary canal. However, open questions include the incidence of species-related differences in beta 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.
Manara
L
L
Research Centre Sanofi Midy SpA, Milan, Italy.
Croci
T
T
Landi
M
M
D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3; D013329:Structure-Activity Relationship
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D022702:Receptors, Adrenergic, beta-3