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

We have previously reported that dual 5-HT _1A and 5-HT ₇ 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 D ₂ receptor. However, SYA16263 also binds with very high affinity to 5-HT _1A R (Ki = 1.1 nM) and a moderate affinity at 5-HT ₇ R (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 _1A R and 5-HT ₇ R 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 _1A R, Ki = 0.74 nM) and a low nanomolar (5-HT ₇ R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT _1A R and antagonist at the 5-HT ₇ R, functional characteristics which point to its potential as an antidepressant agent.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Published by Elsevier Masson SAS.)