Isodrimenine Derivatives Selectively Inhibit Human α7-Containing Nicotinic Acetylcholine Receptors via Negative Allosteric Modulation

Abstract

Drimane sesquiterpenoids are biologically active compounds found in plants, fungi, and marine organisms. Three isodrimeninederivatives, 5,6-dehydro-7-keto-isodrimenine (DH7KID), 7-keto-isodrimenine (7KID), and 7-acetoxy-isodrimenine (7AID), belonging to thedrimane-type sesquiterpene family were synthesized and evaluated foractivity at various human nicotinic acetylcholine receptor (nAChR)subtypes using two-electrode voltage-clamp electrophysiology. All threecompounds exhibited comparable inhibitory potency across nAChRsubtypes but showed greater selectively for α7-containing receptors. ForDH7KID, the selectivity order was α7β2 ≅ α7 > α4β4 > α6*β2β3 (*α6-α3 chimera) > α4β2 ≅ α6*β4 > α3β4 ≅ α3β2 > α9α10. Inhibition of α7and α4β4 nAChRs by DH7KID and 7KID, respectively, was independentof acetylcholine concentration, indicating a noncompetitive mechanismand suggesting that these compounds do not act at the orthosteric site. Furthermore, inhibition was voltage-independent, consistentwith binding to a nonluminal allosteric site. The deactivation time constants of currents mediated by α7- and α4-containing nAChRswere unaffected by isodrimenine. In silico structural analyses further supported the interaction of DH7KID with nonluminal allostericsites on the α7 nAChR. Collectively, these findings demonstrate that isodrimenine derivatives function as negative allostericmodulators of α7-containing nAChRs. Given the biological significance of α7 nAChRs, isodrimenine-induced inhibition may havetherapeutic relevance for neuropsychiatric disorders.