title: Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells.
abstract: Numerous synthetic agonists selectively stimulate beta3-adrenoceptors (ARs). The endogenous catecholamines, noradrenaline and adrenaline, however, stimulate all the beta-AR subtypes, and no selective physiological agonist for beta3-ARs has been described so far. The aim of this study was to investigate whether any naturally occurring amine can stimulate selectively beta3-ARs. Since activation of lipolysis is a well-known beta-adrenergic function, the efficacy and potency of various biogenic amines were compared with those of noradrenaline, isoprenaline, and beta3-AR agonists 4-(-{[2-hydroxy-(3-chlorophenyl)ethyl]-amino} propyl)phenoxyacetate (BRL 37,344) and (R,R)-5-(2-{[2-(3-chlorophenyl )-2-hydroxyethyl]-amino} propyl)-1,3-benzo-dioxole-2,2-dicarboxylate (CL 316,243) by testing their lipolytic action in white fat cells. Five mammalian species were studied: rat, hamster and dog, in which selective beta-AR agonists act as full lipolytic agents, and guinea-pigs and humans, in which beta3-AR agonists are less potent activators of lipolysis. Several biogenic amines were inefficient (e.g. dopamine, tyramine and beta-phenylethylamine) while others (synephrine, phenylethanolamine, epinine) were partially active in stimulating lipolysis in all species studied. Their actions were inhibited by all the beta-AR antagonists tested, including those selective for beta1- or beta2-ARs. Octopamine was the only amine fully stimulating lipolysis in rat, hamster and dog fat cells, while inefficient in guinea-pig or human fat cells, like the beta3-AR agonists. In rat white fat cells, beta-AR antagonists inhibited the lipolytic effect of octopamine with a relative order of potency very similar to that observed against CL 316,243. Competitive antagonism of octopamine effect resulted in the following apparent pA2 [-log(IC50), where IC50 is the antagonist concentration eliciting half-maximal inhibition] values: 7.77 (bupranolol), 6.48 [3-(2-ethyl-phenoxy)-1[(1 S)-1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)2-propanol oxalate, SR 59230A, a beta3-selective antagonist], 6.30[erythro-D,L-1(7-lethylindan-4-yloxy)-3-isopropylamino-+ ++butan-2-ol, ICI 118,551, a beta2-selective antagonist] and 4.71 [(+/-)-[2-(3-carbomyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1- methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]2-propanolmethane sulphonate, CGP 20712A, a beta1-selective antagonist]. Octopamine had other properties in common with beta3-AR agonists: stimulation of oxygen consumption in rat brown fat cells and very low affinity in displacing [3H]CGP 12,177 binding to [beta1- or beta2-ARs in dog and rat adipocyte membranes. In Chinese hamster ovary (CHO) cells expressing human beta3-ARs, octopamine inhibited [125I]ICYP binding with only twofold less affinity than noradrenaline while it exhibited an affinity around 200-fold lower than noradrenaline in CHO cells expressing human beta1- or beta2-ARs. These data suggest that, among the biogenic amines metabolically related to catecholamines, octopamine can be considered as the most selective for beta3-ARs.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 317, Institut Fédératif de Recherches 31, CHU Rangueil, Toulouse, France. carpene@rangueil.inserm.fr
authors.forename: C
authors.initials: C
authors.lastname: Carpéné
authors.forename: J
authors.initials: J
authors.lastname: Galitzky
authors.forename: E
authors.initials: E
authors.lastname: Fontana
authors.forename: C
authors.initials: C
authors.lastname: Atgié
authors.forename: M
authors.initials: M
authors.lastname: Lafontan
authors.forename: M
authors.initials: M
authors.lastname: Berlan
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001667:Binding, Competitive; D001679:Biogenic Amines / Q000494:pharmacology; D002046:Bupranolol / Q000494:pharmacology; D016466:CHO Cells / Q000166:cytology / Q000378:metabolism; D006224:Cricetinae; D004149:Dioxoles / Q000494:pharmacology; D004285:Dogs; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D008322:Mammals / Q000378:metabolism; D008647:Mesocricetus; D009638:Norepinephrine / Q000494:pharmacology; D009655:Octopamine / Q000378:metabolism / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3; D013045:Species Specificity
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000318:Adrenergic beta-Agonists; D001679:Biogenic Amines; D004149:Dioxoles; D004983:Ethanolamines; D007093:Imidazoles; D007457:Iodine Radioisotopes; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D009655:Octopamine; C026777:ICI 118551; C057368:BRL 37344; D020120:Iodocyanopindolol; D002046:Bupranolol; D011433:Propranolol; C049763:CGP 20712A; D007545:Isoproterenol; D009638:Norepinephrine