DM506 (3-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole fumarate), a Novel Derivative of Ibogamine, Inhibits 7 and 910 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(R)interface and another in the & alpha;10(+)/& alpha;9(R) 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.