Nelotanserin

A potent, selective 5-HT2A inverse agonist with pKi of 9.2; displays >30- and 5000-fold selectivity compared with 5-HT2C and 5-HT2B receptors; prevents DOI-induced hypolocomotion and increases sleep consolidation; orally active.Depression Phase 2 Discontinued (In Vitro) :Results from IP accumulation assays suggest that Nelotanserin is a potent 5-HT2A full inverse agonist (IC50=1.7 nM), a moderately potent 5-HT2C partial inverse agonist (IC50=79 nM) (maximal response was 62% of the response obtained for the reference inverse agonist clozapine), and a weak 5-HT2B inverse agonist (IC50=791 nM) . Nelotanserin displays high affinity for recombinant human 5-HT2A receptors (Ki=0.35 nM), moderate affinity for human 5-HT2C receptors (Ki=100 nM), and low affinity for human 5-HT2B receptors (2000 nM) stably expressed in HEK293 cells. The results suggest that Nelotanserin has a 262-fold higher affinity for human 5-HT2A than 5-HT2C receptors and a 6610-fold higher affinity for human 5-HT2A than 5-HT2B receptors. (In Vivo) :Each compound is tested in a minimum of five rats by oral gavage with administration occurring in the middle of the inactive period, 6 h after light onset. The delta power during non-REM sleep (NREMS) is significantly different between all the analogues tested and the vehicle control. Nelotanserin (Compound 39) produces significant increases in delta power that persist for the first 4 h following dosing. Significant differences are found, however, in NREMS bout length. Nelotanserin significantly increases NREMS bout length during the first hour following dosing, and 3 does so during the second hour. In conjunction with this increased NREM bout duration, the number of NREM bouts decrease during the first hour for Nelotanserin (p<0.01) as well as for compound 15 (p<0.05) .