“Methylene Bridge” to 5-HT₃ Receptor Antagonists: Conformationally Constrained Phenylguanidines

Abstract

Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT 3 receptors (e.g., partial agonist, agonist, superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT 3 receptor antagonists. We examined the structure−activity relationships of 1. Replacement/ removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT 3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT 3 receptor antagonist.

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

“…Functional characterization of all the compounds were performed using two-electrode voltage-clamp assay using Xenopus oocytes that expressed α7 receptors as described previously. − Briefly, ovarian lobes were surgically harvested from X. laevis and washed twice in Ca 2+ -free Barth’s solution (82.5 mM NaCl, 2.5 mM KCl, 1 mM MgCl2, and 5 mM HEPES, pH 7.4). These lobes were enzymatically defolliculated to release oocytes by shaking for 90 min in 1.5% collagenase (Sigma-Aldrich) dissolved in Ca 2+ -free Barth’s Buffer.…”

“…This was prepared in the same manner as that of compound 11 from 3iodo-N-methylaniline hydrochloride (25) 20 N-(3-Fluorophenyl)-N-methylguanidine Hydrochloride (13). This was prepared in the same manner as that of compound 11 from 3fluoro-N-methylaniline hydrochloride (26). The residue was recrystallized from i-PrOH to give 22% of the desired product as white crystals: mp 197−199 °C; IR (diamond, cm −1 ): 3123 (NH), 3288 (NH 2 ); 1 N-(3-Trifluoromethyl)-N-methylguanidine Hydrochloride ( 14).…”