New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263

We have previously reported that dual 5-HT_1A and 5-HT₇ receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D₂ receptor. However, SYA16263 also binds with very high affinity to 5-HT_1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT₇R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT_1AR and 5-HT₇R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT_1AR, Ki = 0.74 nM) and a low nanomolar (5-HT₇R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT_1AR and antagonist at the 5-HT₇R, functional characteristics which point to its potential as an antidepressant agent.