L-750355, a human beta3-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 agonist, (S)-N-[4-[2-[[3[(2-amino-5-pyridinyl)oxy]-2-hydroxy-propyl]amino]-eth yl]-phenyl]-4-isopropylbenzenesulfonamide, L-750355, is described. Using cloned human and rhesus beta1-, beta2- and beta3-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%) beta3-adrenoceptors. Furthermore, L-750355 stimulates lipolysis in rhesus adipocytes in vitro. L-750355 is a weak partial agonist (EC(50)=3.2 microM; % maximal receptor activation=33% ) for the human beta1-adrenoceptor but exhibits no agonist activity for rhesus beta1- or beta2-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.
Forrest
M J
MJ
Department of Animal Pharmacology, Merck Research Laboratories (RY80Y-135), P.O. Box 2000, Rahway, NJ 07065-0900, USA. mike_forrest@merck.com
Hom
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Bach
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Candelore
M R
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Cascieri
M A
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Strader
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Tota
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Fisher
M H
MH
Szumiloski
J
J
Ok
H O
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Weber
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Wyvratt
M
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Vicario
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Marko
O
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Deng
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Cioffe
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Hegarty-Friscino
B
B
MacIntyre
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D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000420:Albuterol / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005990:Glycerol / Q000097:blood*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D008253:Macaca mulatta; D011433:Propranolol / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D013610:Tachycardia / Q000097:blood* / Q000139:chemically induced; D000096926:Benzenesulfonamides
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000420:Albuterol; D000631:Aminopyridines; D005990:Glycerol; D007545:Isoproterenol; D011433:Propranolol; D018342:Receptors, Adrenergic, beta-1; D013449:Sulfonamides; C417215:L 750355; D000096926:Benzenesulfonamides