Elaine Ryan

Indanyl piperazines as melatonergic MT2 selective agents

Optimization of a benzyl piperazine pharmacophore produced N-acyl-4-indanyl-piperazines that bind with high affinity to melatonergic MT(2) receptors. (R)-4-(2,3-dihydro-6-methoxy-1H-inden-1-yl)-N-ethyl-1-piperazine-carboxamide fumarate (13) is a water soluble, selective MT(2) agonist, which produces advances in circadian phase in rats at doses of 1-56 mg/kg that are no different from those of melatonin at 1 mg/kg. Unlike melatonin, 13 produced only weak contractile effects in rat tail artery.

Unique modulation of central 5-HT2 receptor binding sites and 5-HT2 receptor-mediated behavior by continuous gepirone treatment

The effect of continuous treatment with the selective 5-HT1A agonist gepirone upon 5-HT2-mediated behavior and cortical 5-HT2 receptor binding sites was examined in naive rats or rats receiving noradrenergic (DSP4) or serotonergic (5,7-DHT) lesions. Continuous administration of gepirone in non-lesioned rats for 3, 7, or 14 days enhanced the head shake response to the 5-HT agonist quipazine. This enhancement of 5-HT2-mediated behavior occurred despite concomitant down-regulation of cortical 5-HT2 binding sites. However, 28 days of gepirone administration significantly reduced behavioral responsiveness to quipazine. The gepirone-induced facilitation of 5-HT2-mediated behavior observed after 7 days of continuous treatment was blocked in both DSP4 and 5,7-DHT-lesioned rats. However, both noradrenergic and serotonergic denervation failed to modify the down-regulation of 5-HT2 receptor binding sites produced by continuous gepirone administration. These results suggest that the curious dissociation of behavioral and biochemical indices of 5-HT2 receptor function produced by continuous gepirone treatment may be the result of a dual yet separate action of the drug on central presynaptic noradrenergic and serotonergic mechanisms and postsynaptic 5-HT receptors. Furthermore, the postsynaptic action of gepirone which reduces the maximal number of cortical 5-HT2 receptor binding sites may be the result of gepirones agonist action at postsynaptic 5-HT1A receptors.