Enzymatic synthesis of capsaicin analogs and their effect on the T-type Ca2+ channels.

Capsaicin (Cap) and its analogs (CAPanalogs) have diverse effects in sensory neurons including analgesia, implying they modulate other cellular targets besides the TRPV1 Cap receptor. Since Cap and CAPanalogs are not largely available and their chemical synthesis is cumbersome, they have been obtained through a direct lipase-catalyzed reaction. Capsiate, the ester CAPanalog, was synthesized using a novel enzymatic transacylation one-pot strategy. Five different CAPanalogs were synthesized by amidation in 2-methyl-2-butanol with higher yields than previously reported. Voltage-dependent Ca(2+) channels (Ca(v)s) are among the main Ca(2+) entry paths into cells. They are classified as high-voltage-activated Ca(2+) channels (HVA) and low-voltage-activated Ca(2+) channels (LVA) constituted only by T-type channels. Though HVA Ca(v)s are Cap sensitive, it is not known if capsaicinoids inhibit LVA Ca(v)s which participate in the primary sensory neuron pain pathway. Here we first report that Cap, dihydrocapsaicin, N-VAMC(8), N-VAMC(9), and N-VAMC(10) can directly and partially reversibly inhibit T-type Ca(v)s, whereas olvanil, capsiate, and vanillylamine cannot. The Cap inhibition of T-type Ca(v)s was independent of TRPV1 activation.