Agonists of the alpha4beta2 nicotinic acetylcholine receptors have been synthesised as potential drugs for treatment of a variety of diseases. In this review, the published nicotinic agonists are presented and, on the basis of the molecular structure, the compounds are divided into three compound classes, nicotinoids (structurally close to nicotine), bicyclic compounds (structurally close to epibatidine and anatoxin-a), and analogues of imidacloprid (structurally close to the insecticide imidacloprid). The structure-activity relationships are discussed within and in between the classes. On the basis of computational studies of ligands for the nicotinic acetylcholine receptors the structure-activity relationships are discussed and a possible binding mode suggested. The binding mode encompasses: (A) an interaction between an anionic site in the receptor and the protonated nitrogen atom in the ligand, (B) a hydrogen bond between a hydrogen bond donor in the receptor and a hydrogen bond acceptor in the ligand, (C) an interaction between a pi-system (heteroaromatic ring, carbonyl bond) in the ligand and another pi-system or a positively charged amino acid residue in the binding site, (D) a pi-cation interaction between aromatic residues in the receptor binding site and the protonated nitrogen atom in the ligand, and (E) steric interactions of positive and negative character around the aliphatic and the heteroaromatic part of the ligand.
A series of 3-(3-substituted-pyrazinyl)-1,2,5,6-tetrahydro-1-methylpyridines were synthesized and found to have high affinity for central muscarinic receptors. The ability of some of these compounds to inhibit the electrically stimulated twitch of the guinea pig vas deferens indicated that the compounds were M1 agonists. M1 agonist activity was related to the length of the side chain attached to the pyrazine ring, with maximal activity being obtained with the hexyloxy side chain. The (hexyloxy)pyrazine 3f lacked M2 agonist activity as it failed to affect the guinea pig atria and was also relatively devoid of M3 agonist activity as determined by its lack of tremorogenic and sialogogic effects in mice. A comparison of the M1 agonist efficacy of these pyrazines and related 1,2,5-thiadiazoles and 1,2,5-oxadiazoles suggested that M1 efficacy was related to the magnitude of electrostatic potential located over the nitrogens of the respective heterocycles. The heteroatom directly attached to the 3 position of the pyrazine or 1,2,5-thiadiazole heterocycle markedly influenced the M1 efficacy of the compounds by determining the energetically favorably conformers for rotation about the bond connecting the tetrahydropyridyl ring and the heterocycle. A three-dimensional model for the M1-activating pharmacophore was proposed based on computational studies and the model of the muscarinic pharmacophore proposed by Schulman.
In an attempt to improve upon the M1 agonist activity of the selective M1 agonist xanomeline and related compounds, the M1 muscarinic efficacies and potencies of 3- and 6-substituted pyrazinylazacycles were varied by changing both the 3- and 6-substituents as well as the azacycle. Significant improvements in efficacy and potency over the previously prepared [3-(hexyloxy)pyrazinyl]tetrahydropyridine 19 were obtained with the [3-(hexyloxy)pyrazinyl]-quinuclidine 5i. The M1 activity of 5i showed some enantioselectivity with (S)-5i being ca. 4-fold more potent than (R)-5i. Like 19 and xanomeline, 5i was a functionally selective M1 agonist that showed greater functional selectivity than widely studied pyrazinylquinuclidine 5n (L-689,660). The improved functional selectivity of 5i over 5n could be attributed to the additional binding interactions between the hexyloxy side chain of 5i and the M1 receptor that are not available to 5n. Although 5i may show M1 functional selectivity comparable to xanomeliine, 5i is a less efficacious and potent M1 agonist than xanomeline.
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