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-DPAT) and buspirone. At human (h) 5-HT1A receptors in CHO cells, RS-30199-193 (racemate) and its enantiomers (-197, -198) inhibited [3H]-8-OH-DPAT binding (RS-30199-198, ki, 29.7 +/- 11.7 nM; RS-30199-197, ki, 74.1 +/- 11.7 nM) as did RS-64459 (ki, 24.9 +/- 6.0 nM), but RS-30199-197 and -198 were almost full agonists in a [35S]-GTPgammaS binding assay, whereas RS-64459 was a partial agonist, resembling buspirone 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 induce the 5-HT behavioural syndrome in male rats. However, in a model where naive male rats were introduced to estrogen-progesterone primed, sexually receptive female rats, RS-30199-197 (0.1, 1, 10 mg/kg, s.c.) had a profound inhibitory effect on sexual behaviour score. Neither buspirone nor 8-OH-DPAT reduced the sexual behaviour score. Unlike 8-OH-DPAT, which shortens intromission latency, RS-30199 prolonged intromission latency. RS-30199 (10 mg/kg s.c.) fully inhibited the facilitation of sexual behaviour caused by the alpha2-adrenoceptor antagonist, delequamine (0.1 mg/kg, p.o.). In contrast, RS-64459 (100, 250, 1000 and 4000 microg/kg, s.c.) failed to modify the sexual behaviour score and did not modify intromission latency. The differences between the effects of RS-30199 and RS-64459 in binding and functional experiments are supported by molecular models of the receptor-ligand interaction, where the compounds interact in different ways with the receptor; a model is 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.
Institut de Internationales, Servier, Croissy Research Centre, Paris, France. spedding@servier.fr
M
M
Spedding
A
A
Newman-Tancredi
M J
MJ
Millan
C
C
Dacquet
A N
AN
Michel
E
E
Jacoby
B
B
Vickery
D
D
Tallentire
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D005260:Female; D006801:Humans; D007546:Isoquinolines; D008297:Male; D008956:Models, Chemical; D009281:Naphthalenes / Q000494:pharmacology*; D009287:Naphthyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012726:Sexual Behavior, Animal / Q000187:drug effects*
D000317:Adrenergic alpha-Antagonists; D014151:Anti-Anxiety Agents; D001381:Azepines; D007546:Isoquinolines; D009281:Naphthalenes; D009287:Naphthyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C073364:RS 30199-193; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C060956:Delequamine