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

Year: 2025

Type: article

Abstract: 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. In silico 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.

Source: ACS Chemical Neuroscience

DOI: 10.1021/acschemneuro.5c00862