Pharmacology and quantitative structure-activity relationships of imidazolylpropylguanidines with mepyramine-like substructures as non-peptide neuropeptide Y Y1receptor antagonists

Abstract

The design of non-peptide, Y1-selective antagonists of neuropeptide Y (NPY) as pharmacological tools is in progress and is increasingly important as therapeutic applications are expected. Starting from the potent histamine H2agonist and weak NPY Y1antagonist arpromidine, 16 imidazolylpropylguanidine derivatives were synthesized and tested for Y1antagonistic activity (inhibition of NPY-stimulated Ca2+increase in human erythroleukemic cells), where the pheniramine-like moiety of arpromidine was replaced with 2-pyridylaminoalkyl, benzyl-(2-pyridyl)aminoalkyl, and phenyl-(2-pyridyl)alkylaminoalkyl partial structures derived from mepyramine. The pA2values of the most active compounds are in the range of 6.2-6.5. Quantitative structure-activity relationships (QSAR) were investigated by fragment regression analysis. Results indicate that a tetramethylene spacer between the guanidino group and the amino nitrogen is optimal. For an at least moderate degree of Y1antagonistic activity, a second benzyl or phenyl group must be present in addition to the 2-pyridyl ring. At this second group, hydrophobic substituents such as 3,4-di-Cl and 4-Br further enhance Y1antagonism. The most active derivative additionally bears a 5-Br substituent at the 2-pyridyl moiety. Structure-activity relationships suggest that the compounds might be able to partially imitate the role of NPY when interacting with Y1receptors and thus behave as moderate non-peptide NPY Y1antagonists.Key words : neuropeptide Y Y1antagonists, imidazolylpropylguanidines, quantitative structure-activity relationships.