L-750355, a human ß3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey

Abstract

The profile of in vitro and in vivo biology of a human ß3-adrenoceptor agonist, ( S)- N-[4-[2-[[3[(2-amino-5-pyridinyl)oxy]-2-hydroxy-propyl]amino]-ethyl]-phenyl]-4-isopropylbenzenesulfonamide, L-750355, is described. Using cloned human and rhesus ß1-, ß2- and ß3-adrenoceptors, expressed in Chinese hamster ovary (CHO) cells, L-750355 was shown to be a potent, albeit partial, agonist for the human (EC 50=10 nM; % maximal receptor activation=49%) and rhesus (EC 50=28 nM; % maximal receptor activation=34%) ß3-adrenoceptors. Furthermore, L-750355 stimulates lipolysis in rhesus adipocytes in vitro. L-750355 is a weak partial agonist (EC 50=3.2 μM; % maximal receptor activation=33% ) for the human ß1-adrenoceptor but exhibits no agonist activity for rhesus ß1- or ß2-adrenoceptors of either human or rhesus origin. Administration of L-750355 to anesthetized rhesus monkeys, as a series of rising dose intravenous infusions, evokes dose-dependent glycerolemia and tachycardia with no change in mean arterial blood pressure or plasma potassium. The dose–response curve for L-750355-induced glycerolemia lies to the left of that for tachycardia. Propranolol, at a dose (0.3 mg/kg, i.v.) that attenuates isoproterenol-induced changes in heart rate and glycerolemia, abolished L-750355-induced tachycardia but had no effect on L-750355-induced glycerolemia.