A two-state model for the 5-HT2 receptor: effects of alpha-adrenoceptor ligands.

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.