L-750355, a human beta 3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey

The profile of in vitro and in vivo biology of a human beta3-adrenoceptor a gonist, (S)-N-[4-[2-[[3[(2-amino-5-pyridinyl)oxyy]-2-hydroxy- propyl]amino] -ethyl]-phenyl]-4-isopropylbenzenesulfonamide, L-750355, is described. Usin g cloned human and rhesus beta1-, beta2- and beta3-adrenoceptors, expressed in Chinese hamster ovary (CHO) cells, L-750355 was shown to be a potent, a lbeit partial, agonist for the human (EC50 = 10 nM; % maximal receptor acti vation = 49%) and rhesus (EC50 = 28 nM; % maximal receptor activation = 34% ) beta3-adrenoceptors. Furthermore, L-750355 stimulates lipolysis in rhesus adipocytes in vitro. L-750355 is a weak partial agonist (EC50 = 3.2 muM; % maximal receptor activation = 33%) for the human beta1-adrenoceptor but ex hibits no agonist activity for rhesus beta1- or beta2-adrenoceptors of eith er human or rhesus origin. Administration of L-750355 to anesthetized rhesu s monkeys, as a series of rising dose intravenous infusions, evokes dose-de pendent 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 do se (0.3 mg/kg, i.v.) that attenuates isoproterenol-induced changes in heart rate and glycerolemia, abolished L-750355-induced tachycardia but had no e ffect on L-750355-induced glycerolemia. (C) 2000 Elsevier Science B.V. All rights reserved.