TY - JOUR

T1 - Discovery of a Novel Class of Benzimidazole-Based Nicotinic Acetylcholine Receptor Modulators

T2 - Positive and Negative Modulation Arising from Overlapping Allosteric Sites

AU - Zhou, Libin

AU - Dau, Vidan

AU - Jensen, Anders A

PY - 2023

Y1 - 2023

N2 - Here, we present the discovery of a novel class of benzimidazole-based allosteric modulators of nicotinic acetylcholine receptors (nAChRs). The modulators were developed based on a compound (1) exhibiting positive modulatory activity at α4β2 nAChR in a compound library screening by functional characterization of 100 analogues of 1 at nAChRs. Two distinct series of positive and negative allosteric modulators (PAMs and NAMs, respectively) comprising benzimidazole as a shared structural moiety emerged from this SAR study. The PAMs mediated weak modulation of α4β2 and α6β2β3, whereas the NAMs exhibited essentially equipotent inhibition of α4β2, α6β2β3, α6β4β3, and α3β4 nAChRs, with analogue 9j [2-(2,4-dichlorophenoxy)-1,3-dimethyl-1-H-benzo[d]imidazole-3-ium] displaying high-nanomolar and low-micromolar IC50 values at the β2- and β4-containing receptor subtypes, respectively. We propose that the PAMs and NAMs act through overlapping sites in the nAChR, and these findings thus underline the heterogenous modes of modulation that can arise from a shared allosteric site in the receptor.

AB - Here, we present the discovery of a novel class of benzimidazole-based allosteric modulators of nicotinic acetylcholine receptors (nAChRs). The modulators were developed based on a compound (1) exhibiting positive modulatory activity at α4β2 nAChR in a compound library screening by functional characterization of 100 analogues of 1 at nAChRs. Two distinct series of positive and negative allosteric modulators (PAMs and NAMs, respectively) comprising benzimidazole as a shared structural moiety emerged from this SAR study. The PAMs mediated weak modulation of α4β2 and α6β2β3, whereas the NAMs exhibited essentially equipotent inhibition of α4β2, α6β2β3, α6β4β3, and α3β4 nAChRs, with analogue 9j [2-(2,4-dichlorophenoxy)-1,3-dimethyl-1-H-benzo[d]imidazole-3-ium] displaying high-nanomolar and low-micromolar IC50 values at the β2- and β4-containing receptor subtypes, respectively. We propose that the PAMs and NAMs act through overlapping sites in the nAChR, and these findings thus underline the heterogenous modes of modulation that can arise from a shared allosteric site in the receptor.

U2 - 10.1021/acs.jmedchem.3c01185

DO - 10.1021/acs.jmedchem.3c01185

M3 - Journal article

C2 - 37650525

VL - 66

SP - 12586

EP - 12601

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -