Efficiency of open channel blockers of neuronal nicotinic acetylcholine receptors as estimated from the structure/activity relationship

摘要

The participation of definite molecular fragments of bis-cationic ammonium compounds in their blocking effect upon neuronal nicotinic acetylcholine receptors (nAChRs) was deduced from the relationship between the blocking efficacy and three-dimensional molecular models of such compounds that have different fragments. The data on the structure and activity of 15 channel blockers were used for this purpose; predicted blocking effects of the substances were calculated. The correlation coefficients between the blocking activity of the compounds and their predicted efficacy were statistically significant (P > 0.95). The results suggest that HCNCCCCCNCH and HCCNCCCCCNCH fragments (atom chains) with the dimensions of 1.42 and 1.36 nm, respectively, provide the most positive contribution, while a HCNCCCCCNCH fragment with the dimension of 1.36 nm corresponds to highly negative contribution to the blocking activity of compounds. Using the data obtained, we identified the optimum compound structures. The mechanism of the blocking effect upon nAChRs is discussed.