N₁H- and N₁-Substituted Phenylguanidines as α7 Nicotinic Acetylcholine (nACh) Receptor Antagonists: Structure–Activity Relationship Studies

Abstract

We previously reported that N-(3-chlorophenyl)­guanidine (1) represents a novel α7 nicotinic ACh (nACh) receptor antagonist chemotype. In the present study, a small series of compounds was synthesized with the intent to investigate the structure–activity relationship (SAR). Preliminary data suggested that the N-methyl analog of 1, 2, was several times more potent. Therefore, the chloro group at the aryl 3-position of 1 and its N1-methyl counterpart 2 were replaced with a number of substituents considering the electronic, lipophilic, and steric nature of the substituents. The potencies of the compounds to inhibit acetylcholine (ACh)-induced responses were obtained in Xenopus laevis oocytes expressing human α7 nicotinic ACh receptors (nAChRs) using a two-electrode voltage-clamp assay. We found that the nature of the 3-position substituents had relatively little (i.e., <10-fold) effect on potency, and the presence of an N1-isopropyl substituent was tolerated. Here, we report the first SAR investigation of this novel α7 nAChR antagonist chemotype.

Targeting Alpha7 Nicotinic Acetylcholine Receptors in Lung Cancer: Insights, Challenges, and Therapeutic Strategies

“…APS8 can also block α4β2 nAChR, although its affinity for α7 nAChR is high . Together with, MD-354 and compound 12, its N -methyl analogue containing a novel phenyl guanidine scaffold, were reported as noncompetitive α7 nAChR antagonists. , In the rat brain, compound 12 can compete [ 125 I]-bungarotoxin in the cerebral cortex, hippocampus, and hypothalamic mammillary nuclei, that express α7 nAChR . However, the modification barely increases the α7 nAChR potency.…”

“…107,108 In the rat brain, compound 12 can compete [ 125 I]-bungarotoxin in the cerebral cortex, hippocampus, and hypothalamic mammillary nuclei, that express α7 nAChR. 107 However, the modification barely increases the α7 nAChR potency. Moreover, indinavir, which is an approved drug for noncancer diseases, can exhibit α7 nAChR antagonist effects.…”