Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative,with 5-HT1, receptor subtypes in the rat brain

Summary Isamoltane (CGP 361A; (1-(2-(1-pyrrolyl)phenoxy)-3-isopropylamino-2-propanol hydrochloride), -adrenoceptor ligand (IC₅₀ = 8.4 nmol/l) which has reported activity as an anxiolytic in man was found to be a reasonably active inhibitor of the binding of ¹²⁵I]ICYP to 5-HT_1B recognition sites in rat brain membranes with 27-fold selectivity (IC₅₀ = 39 nmol/l) as compared to the inhibition of binding of ³H]8-OH-DPAT to 5-HT_1A receptors (IC₅₀ = 1070 nmol/l). This selectivity was considerably greater than that observed for other -adrenoceptor ligands including propranolol (5-HT_1A/5-HT_1B ratio = 2), oxprenolol (3.5) and cyanopindolol (8.7). The 5-HT_1B activity of the compound resided in the (–)-enantiomer. (–)Isamoltane had weak activity (IC₅₀ 3–10 mol/l) at 5-HT₂ and ₁-adrenoceptors. The compound was devoid of activity at a number of other central neurotransmitter recognition sites including the 5-HT_1C site. Isamoltane increased the electrically evoked release of ³H]5-HT from prelabeled rat cortical slices in a manner similar to that of cyanopindolol. While both compounds were similar in potency to methiothepin, they had lower efficacy. Oxprenolol was less potent that both isamoltane and cyanopindolol while propranolol was essentially inactive. The effects of the compounds on 5-HT release appeared to be correlated with their 5-HT_1B rather than 5-HT_1A activity. In vivo, isamoltane increased 5-HTP accumulation in rat cortex following central decarboxylase inhibition at doses of 1 and 3 mg/kg i. p. At higher doses this effect was gradually diminished. Similar, but less clearcut results were obtained with cyanopindolol and oxprenolol, but propranolol was ineffective. No changes in brain tryptophan levels were associated with the isamoltaneevoked changes in brain 5-HTP levels. In reserpinized animals, isamoltane reduced 5-HTP accumulation even at doses which enhanced accumulation of this metabolite when given alone. The effects of the putative 5-HT_1B agonist, m-trifluoromethylphenylpiperazine (TFMPP), the mixed 5-HT autoreceptor agonist/antagonist/ -adrenoceptor antagonist, pindolol, the 5-HT uptake inhibitor, CGP 6085A and the MAO-A inhibitor, brofaromine, were not antagonized by pretreatment with isamoltane. The possibility that isamoltane and the other -adrenoceptor antagonists are antagonists at 5-HT_1B receptors and that their effect on 5-GT synthesis in vivo is the net result of their agonist/antagonist effects at 5-HT_1A and 5-HT_1B receptors is discussed in relation to the potential mechanism of the anxiolytic activity of isamoltane.Abbreviations 5-HT Serotonin - ICYP Iodocyanopindolol - 8-OHDPAT 8-hydroxy-2(di-n-propylamino) tetralin - TFMPP m-trifluoromethylphenylpiperazine - MAO-A monoamine oxidase-A Send offprint requests to P. C. Waldmeier at the above address