title: A two-state model for the 5-HT2 receptor: effects of alpha-adrenoceptor ligands.
abstract: The mode of interaction of some alpha-adrenoceptor ligands with the 5-HT2-receptor system was investigated in the calf coronary artery. Isometric contractions caused by 5-hydroxytryptamine (5-HT) were studied on strips without endothelium. Phentolamine antagonized competitively (pKB = 7.4) the effects of 5-HT. Phentolamine also prevented the methysergide-induced depression of contractions elicited by 5-HT. The alpha 1-selective ligand 127I-HEAT depressed the responses to 5-HT. Both phentolamine and ketanserin prevented the depressant effects of I-HEAT on 5-HT-induced contractions. These and previous experiments are consistent with the existence of the 5-HT2 receptor in two interconvertible states R in equilibrium with R'. Interconversions between the high affinity state R and low affinity state R' (for 5-HT) appear to be modulated by an allosteric site A. The present and previous data suggest four possible modes of interaction of alpha-adrenoceptor ligands with the 5-HT2-receptor system: (a) ligands that compete with 5-HT for the 5-HT2 receptor in the R state (examples are nonselective phentolamine, alpha 1-selective ketanserin and corynanthine, and alpha 2-selective yohimbine and rauwolscine); (b) ligands such as I-HEAT that through binding to A depress the response to 5-HT by favouring the R' state; (c) ligands, such as ketanserin and phentolamine, that through binding to A favour the R state; and (d) ligands, such as phenoxybenzamine, that cause a covalent modification of the R state but not of the R' state. Qualitative and quantitative considerations suggest that in the calf coronary artery the described features are unrelated to alpha 1- and alpha 2-adrenoceptors.
authors: ICI Pharmaceuticals Division, Mereside, Macclesfield, Cheshire, U.K.
authors: A J
authors: AJ
authors: Kaumann
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D003331:Coronary Vessels / Q000378:metabolism; D007650:Ketanserin / Q000494:pharmacology; D008784:Methysergide / Q000494:pharmacology; D009119:Muscle Contraction; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism; D010646:Phentolamine / Q000494:pharmacology; D011941:Receptors, Adrenergic / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D044024:Tetralones
chemical_list: D010627:Phenethylamines; D011941:Receptors, Adrenergic; D011985:Receptors, Serotonin; D044024:Tetralones; D012701:Serotonin; C048008:2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl)tetralone; D007650:Ketanserin; D008784:Methysergide; D010646:Phentolamine