Design and discovery of a high affinity, selective and β-arrestin biased 5-HT Receptor Agonist.

Compound , 5-chloro-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-2,3-dihydro-1H-inden-1-one was previously reported from our laboratory showing high affinity binding to the 5-HT receptor ( = 0.5 nM). However, compound racemizes readily upon enantiomeric separation. To prevent racemization, we have redesigned and synthesized methyl and carboxyethyl analogs, compounds and respectively, whose binding affinities were similar to those of compound . Compounds and cannot undergo racemization since tautomerism was no longer possible and thus, compound was selected for enantiomeric separation and further evaluation. Upon enantiomeric separation, the levorotatory enantiomer, (-) or 2 demonstrated a higher affinity ( = 1.2 nM) than the or enantiomer ( = 93 nM) and a β-arrestin biased functional selectivity for the 5-HT receptor. Although showed about 8 times less activity than 5-HT in the Gs pathway, it showed over 31 times higher activity than 5-HT in the β-arrestin pathway. This constitutes a significant β-arrestin pathway preference and shows to be more potent and more efficacious than the recently published β-arrestin biased 3-(4-chlorophenyl)-1,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine, the N-debenzylated analog of JNJ18038683 (Compound .