The computational design of amidines as H 2-receptor agonists. The reduction of the amidine group basicity in N-methylformamidine analogues

Abstract

In a previous study, we explored the use of an amidine group as a replacement of histamine's imidazole ring in the context of a previously proposed model of recognition and activation at the HZ receptor. We concluded that the unsubstituted acyclic formamidine group, as opposed to the amine group, in N-(3-aminopropyl)formamidine (NAPF) would be preferentially protonated, a condition that is contrary to the requirements of the HZ-receptor model; however, NAPF (with the primary site of protonation arbitrarily assumed to be the amino group) was shown to be useful in testing the model. In the present study, we computationally examine analogues of N-methylformamidine (in various isomeric and tautomeric forms) as a model of NAPF to determine which modifications of the amidine group are necessary to lower its basicity (as measured by proton affinities). These derivatives are substituted at an amidine carbon atom or nitrogen position (preserving the possibility of tautomerism) with functional groups of varying electron-withdrawing strengths. At the Hartree-Fock and second-order Møller-Plesset levels of theory, the calculations reveal that some of the analogues possess a comparable or lower proton affinity than that of a model of NAPF's amino alkyl side-chain (i.e. methylamine) and, at the same time, exist to a significant degree as the N1-H tautomer in the neutral state; both of these attributes are required by the proposed HZ-receptor model. Thus it seems possible to design such amidines as HZ-receptor agonists. We show that the proton affinities are correlated with the electronic effects of the substituents and with the energy difference between the N1-H and N3-H tautomers. Additional calculations on amine-protonated analogues of the compounds studied herein are necessary to determine whether the protonated form exists at a significant level as the N3-H tautomer, as required by the proposed model.