DM506 (3-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a Novel Derivative of Ibogamine, Inhibits α7 and α9α10 Nicotinic Acetylcholine Receptors by Different Allosteric Mechanisms

The main objective of this studywas to determine thepharmacologicalactivity and molecular mechanism of action of DM506 (3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a novel ibogamine derivative, at differentnicotinic acetylcholine receptor (nAChR) subtypes. The functionalresults showed that DM506 neither activates nor potentiates but inhibitsACh-evoked currents at each rat nAChR subtype in a non-competitivemanner. The receptor selectivity for DM506 inhibition follows thesequence: & alpha;9 & alpha;10 (IC50 = 5.1 & PLUSMN; 0.3 & mu;M) approximately equal to & alpha;7 & beta;2 (5.6 & PLUSMN; 0.2 & mu;M) & SIM; & alpha;7(6.4 & PLUSMN; 0.5 & mu;M) > & alpha;6/& alpha;3 & beta;2 & beta;3 (25 & PLUSMN; 1 & mu;M) > & alpha;4 & beta;2 (62 & PLUSMN; 4 & mu;M) approximately equal to & alpha;3 & beta;4 (70 & PLUSMN; 5 & mu;M). No significance differencesin DM506 potency were observed between rat and human & alpha;7 and & alpha;9 & alpha;10 nAChRs. These results also indicated that the & beta;2subunit is not involved or is less relevant in the activity of DM506at the & alpha;7 & beta;2 nAChR. DM506 inhibits the & alpha;7 and & alpha;9 & alpha;10nAChRs in a voltage-dependent and voltage-independent manner, respectively.Molecular docking and molecular dynamics studies showed that DM506forms stable interactions with a putative site located in the & alpha;7cytoplasmic domain and with two intersubunit sites in the extracellular-transmembranejunction of the & alpha;9 & alpha;10 nAChR, one located in the & alpha;10(+)/& alpha;10()interface and another in the & alpha;10(+)/& alpha;9() interface.This study shows for the first time that DM506 inhibits both & alpha;9 & alpha;10and & alpha;7 nAChR subtypes by novel allosteric mechanisms likelyinvolving modulation of the extracellular-transmembrane domain junctionand cytoplasmic domain, respectively, but not by direct competitiveantagonism or open channel block.

Automated summary

The study aimed to investigate the pharmacological activity and molecular mechanism of a novel ibogamine derivative, DM506, on different subtypes of nicotinic acetylcholine receptors (nAChRs). The results showed that DM506 inhibits ACh-evoked currents at rat nAChR subtypes in a non-competitive manner. The inhibition selectivity of DM506 follows a specific sequence, and it interacts with specific sites on the nAChRs. This study reveals that DM506 inhibits both α9α10 and α7 nAChR subtypes through novel allosteric mechanisms, involving modulation of extracellular-transmembrane and cytoplasmic domains.