LB50053: A 5-Hydroxytryptamine_1A Agent with a High Binding Affinity and a Potency Evoking a K⁺ Current

Abstract

The newly synthesized N-substituted derivative of 3-arylpyrrolidine LB50053, 2--butyl}-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, was studied in receptor-binding assays and in electrophysiological measurements. Competitive binding experiments with various radioligands to the rat forebrain revealed that the (S)-enantiomer of LB50053 had a high affinity (K_i 4.2 nmol/l) and a high selectivity for 5-HT_1A receptors as compared with 5-HT_2A, D₁ dopamine, D₂ dopamine, or α₂-adrenergic receptor. In Xenopus oocytes, where coupling of the 5-HT_1A receptor to the G protein activated inwardly rectifying K⁺ channel 1 (GIRK1) was established, (S)-LB50053 evoked an inward K⁺ current through GIRK1 in a manner consistent with a partial agonism. The K_d value deduced from the dose-response relationships of the 5-HT_1A receptor full agonist 8-OH-2-(di-n-propylamino)-1,2,3,4-tetrahydronaphthalene and (S)-LB50053 according to Waud analysis was 64.60 nmol/l. These results demonstrate that LB50053 is a 5-HT_1A receptor partial agonist and thus can be used as a therapeutic or pharmacological research tool for 5-HT_1A receptor mediated events in the future.