title: L-750355, a human beta3-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 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.
authors.affiliation: Department of Animal Pharmacology, Merck Research Laboratories (RY80Y-135), P.O. Box 2000, Rahway, NJ 07065-0900, USA. mike_forrest@merck.com
authors.forename: M J
authors.initials: MJ
authors.lastname: Forrest
authors.forename: G
authors.initials: G
authors.lastname: Hom
authors.forename: T
authors.initials: T
authors.lastname: Bach
authors.forename: M R
authors.initials: MR
authors.lastname: Candelore
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: C
authors.initials: C
authors.lastname: Strader
authors.forename: L
authors.initials: L
authors.lastname: Tota
authors.forename: M H
authors.initials: MH
authors.lastname: Fisher
authors.forename: J
authors.initials: J
authors.lastname: Szumiloski
authors.forename: H O
authors.initials: HO
authors.lastname: Ok
authors.forename: A E
authors.initials: AE
authors.lastname: Weber
authors.forename: M
authors.initials: M
authors.lastname: Wyvratt
authors.forename: P
authors.initials: P
authors.lastname: Vicario
authors.forename: O
authors.initials: O
authors.lastname: Marko
authors.forename: L
authors.initials: L
authors.lastname: Deng
authors.forename: C
authors.initials: C
authors.lastname: Cioffe
authors.forename: B
authors.initials: B
authors.lastname: Hegarty-Friscino
authors.forename: E
authors.initials: E
authors.lastname: MacIntyre
mesh_terms: 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
chemical_list: 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