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

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