The aim of this study was to determine the anti-hypersensitivity activity of novel non-hallucinogenic compounds derived from iboga alkaloids (i.e., ibogalogs), including tabernanthalog (TBG), ibogainalog (IBG), and ibogaminalog (DM506), using mouse models of neuropathic (Chronic Constriction Injury; CCI) and visceral pain (dextrane sulfate sodium; DSS). Ibogalogs decreased mechanical hyperalgesia and allodynia induced by CCI in a dose- and timeframe-dependent manner, where IBG showed the longest anti-hyperalgesic activity at a comparatively lower dose, whereas DM506 displayed the quickest response. These compounds also decreased hypersensitivity induced by colitis, where DM506 showed the longest activity. To understand the mechanisms involved in these effects, two approaches were utilized: ibogalogs were challenged with the 5-HT2A receptor antagonist ketanserin and the pharmacological activity of these compounds was assessed at the respective 5-HT2A, 5-HT6, and 5-HT7 receptor subtypes. The behavioral results clearly demonstrated that ketanserin abolishes the pain-relieving activity of ibogalogs without inducing any effect per se, supporting the concept that 5-HT2A receptor activation, but not inhibition, is involved in this process. The functional results showed that ibogalogs potently activate the 5-HT2A and 5-HT6 receptor subtypes, whereas they behave as inverse agonists (except TBG) at the 5-HT7 receptor. Considering previous studies showing that 5-HT6 receptor inhibition, but not activation, and 5-HT7 receptor activation, but not inhibition, relieved chronic pain, we can discard these two receptor subtypes as participating in the pain-relieving activity of ibogalogs. The potential involvement of 5-HT2B/2 C receptor subtypes was also ruled out. In conclusion, the anti-hypersensitivity activity of ibogalogs in mice is mediated by a mechanism involving 5-HT2A receptor activation.

The main objective of this study was to determine the pharmacological activity 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 different nicotinic acetylcholine receptor (nAChR) subtypes. The functional results showed that DM506 neither activates nor potentiates but inhibits ACh-evoked currents at each rat nAChR subtype in a non-competitive manner. The receptor selectivity for DM506 inhibition follows the sequence: α9α10 (IC50 = 5.1 ± 0.3 μM) ≅ α7β2 (5.6 ± 0.2 μM) ∼ α7 (6.4 ± 0.5 μM) > α6/α3β2β3 (25 ± 1 μM) > α4β2 (62 ± 4 μM) ≅ α3β4 (70 ± 5 μM). No significance differences in DM506 potency were observed between rat and human α7 and α9α10 nAChRs. These results also indicated that the β2 subunit is not involved or is less relevant in the activity of DM506 at the α7β2 nAChR. DM506 inhibits the α7 and α9α10 nAChRs in a voltage-dependent and voltage-independent manner, respectively. Molecular docking and molecular dynamics studies showed that DM506 forms stable interactions with a putative site located in the α7 cytoplasmic domain and with two intersubunit sites in the extracellular-transmembrane junction of the α9α10 nAChR, one located in the α10(+)/α10(─) interface and another in the α10(+)/α9(─) interface. This study shows for the first time that DM506 inhibits both α9α10 and α7 nAChR subtypes by novel allosteric mechanisms likely involving modulation of the extracellular-transmembrane domain junction and cytoplasmic domain, respectively, but not by direct competitive antagonism or open channel block.