BETA(3)-ADRENOCEPTORS AND INTESTINAL MOTILITY

Early substantial evidence of the low susceptibility to beta-adrenocep tor antagonists of non alpha-adrenergic responses reducing gut motilit y and tone was reluctantly accepted as indicating a third beta-recepto r subtype different from the beta(1) and beta(2). This applied likewis e to lipolysis until new selective ''lipolytic'' beta-agonists poorly effective at established beta-receptors were introduced. Shortly after wards these ''lipolytic'' as well as certain newer and even more selec tive beta-adrenoceptor agonists were shown to be potent inhibitors of intestinal motility. The latter are the ''gut-specific'' phenylethanol aminotetralins whose availability as pure isomers attested to the stri ngent stereochemical requirements for selectivity at non-beta(1), non- beta(2) beta-adrenoceptors. Acceptance of the functionally based conce pt of a beta 3-adrenoceptor was boosted on structural grounds by molec ular biology studies. Sequence analysis indicated the existence in hum ans and rodents of genes coding for a third subtype of beta-receptor t hat, when expressed in transfected heterologous cells, had a pharmacol ogical profile distinct from the previously established subtypes. Fina lly, aryloxypropanolaminotetralins have been prepared as the first sel ective antagonists of beta(3)-adrenoceptors, thus providing unambiguou s conclusive evidence of the distinctive functional features of those abundant in the rat colon. The therapeutic potential in gastroenterolo gy of the newer compounds targetable on the beta(3)-adrenoceptor is su ggested by their potent intestinal action in vivo in animal models wit hout any of the cardiovascular or other unwanted effects of convention al beta-adrenoceptor agonists and antagonists, and by the clinically c onfirmed importance of beta-adrenergic control of motor function throu ghout the alimentary canal. However, open questions include the incide nce of species-related differences in beta(3)-adrenoceptors, and as ye t there are no data on gastrointestinal functions in humans under the influence of drugs designed to act selectively at these receptors.