INTERACTION OF THE ANXIOGENIC AGENT, RS-30199, WITH 5-HT1A RECEPTORS - MODULATION OF SEXUAL-ACTIVITY IN THE MALE-RAT

RS-30199 has been shown previously to have atypical interactions at 5- HT1A receptors. RS-30199 and RS-64459, an analogue of buspirone with a buspirone side chain: were compared with the classic, partial agonist at 5-HT1A receptors, 8-hydroxy-2 (di-n-propylamino) tetralin (8-OH-DP AT) and buspirone. At human (h) 5-HT1A receptors in CHO cells. RS-3019 9-193 (racemate) and its enantiomers (-197, -198) inhibited [H-3]-8-OH -DPAT binding (RS-30199-198, k(i), 29.7 +/- 11.7 nM; RS-30199-197, k(i ), 74.1 +/- 11.7 nM) as did RS-64459 (k(i), 24.9 +/- 6.0 nM), but RS-3 0199-197 and -198 were almost full agonists in a [S-35]-GTP gamma S bi nding assay, whereas RS-64459 was a partial agonist, resembling buspir one and 8-OH-DPAT. RS-64459 and the enantiomers of RS-30199 had weaker affinity for 5-HT2C and 5-HT7 receptors. These compounds did not indu ce the 5-HT behavioural syndrome in male rats. However, in a model whe re naive male rats were introduced to estrogen-progesterone primed, se xually receptive female rats, RS-30199-197 (0.1, 1, 10 mg/kg, s.c.) ha d a profound inhibitory effect on sexual behaviour score. Neither busp irone nor 8-OH-DPAT reduced the sexual behaviour score. Unlike 8-OH-DP AT, which shortens intromission latency, RS-30199 prolonged intromissi on latency. RS-30199 (10 mg/kg s.c.) fully inhibited the facilitation of sexual behaviour caused by the alpha(2)-adrenoceptor antagonist, de lequamine (0.1 mg/kg, p.o.). In contrast, RS-64459 (100, 250, 1000 and 4000 mu g/kg, s.c.) failed to modify the sexual behaviour score and d id not modify intromission latency. The differences between the effect s of RS-30199 and RS-64459 in binding and functional experiments are s upported by molecular models of the receptor-ligand interaction, where the compounds interact in different ways with the receptor; a model i s proposed for the allosteric interaction of different agents with the receptor, resulting in different functional profiles. RS-30199 can be considered an atypical agonist at 5-HT1A receptors. (C) 1998 Elsevier Science Ltd. All rights reserved.