title: Stereospecific synthesis and bio-activity of novel beta(3)-adrenoceptor agonists and inverse agonists.
abstract: Since it is widely distributed into the body, beta(3)-adrenoceptor is becoming an attractive target for the treatment of several pathologies such as obesity, type 2 diabetes, metabolic syndrome, cachexia, overactive bladder, ulcero-inflammatory disorder of the gut, preterm labour, anxiety and depressive disorders, and heart failure. New compounds belonging to the class of arylethanolamines bearing one or two stereogenic centres were prepared in good yields as racemates and optically active forms. They were, then, evaluated for their intrinsic activity towards beta(3)-adrenoceptor and their affinity for beta(1)- and beta(2)-adrenergic receptors. Stereochemical features were found to play a crucial role in determining the behaviour of such compounds. In particular, alpha-racemic, (alphaR)- and (alphaS)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}-2- methylpropanoic acid, (alpha-rac, beta-rac)-, (alphaR, betaS)- and (alphaR, betaR)- 2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid were found to be endowed with beta(3)-adrenoceptor agonistic activity. Whereas, (alphaS, betaS)- and (alphaS, betaR)-2-{4-[2-(2-hydroxy-2-phenylethylamino)ethyl]phenoxy}propanoic acid behaved as beta(3)-adrenoceptor inverse agonists. Such compounds showed no affinity for beta(1)- and beta(2)-adrenergic receptor, respectively. Thus, resulting highly selective beta(3)-adrenoceptor ligands.
authors: Dipartimento Farmaco-Chimico, Università di Bari, Via E.Orabona 4, 70125 Bari, Italy.
authors: Maria Grazia
authors: MG
authors: Perrone
authors: Ernesto
authors: E
authors: Santandrea
authors: Laura
authors: L
authors: Bleve
authors: Paola
authors: P
authors: Vitale
authors: Nicola Antonio
authors: NA
authors: Colabufo
authors: Ralf
authors: R
authors: Jockers
authors: Ferdinando Maria
authors: FM
authors: Milazzo
authors: Anna Floriana
authors: AF
authors: Sciarroni
authors: Antonio
authors: A
authors: Scilimati
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D054314:Drug Inverse Agonism; D006801:Humans; D015394:Molecular Structure; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D022702:Receptors, Adrenergic, beta-3; D000242:Cyclic AMP; D000262:Adenylyl Cyclases