H-3 RECEPTOR ANTAGONISTS - CONFORMATIONAL-ANALYSIS OF THIOPERAMIDE AND X-RAY CRYSTAL-STRUCTURE OF THE ANALOG N-CYCLOHEXYL-4-METHYLPIPERIDINE-1-CARBOTHIOAMIDE

Thioperamide yl-4-[4(5)-imidazolyl]piperidine-1-carbothioamide) is a p otent H-3-receptor antagonist, the low conformational flexibility of w hich could be a favourable feature in the design of new H-3-receptor a ntagonists using its structure as a template. Minimum-energy conformat ions of thioperamide were studied with the molecular mechanics approac h, integrated by X-ray cristallography on an analogue, N-cyclohexyl-4- methylpiperidine-1-carbothioamide (1). Compound 1 was synthesized, and its structure has been solved by X-ray diffraction in order to verify the conformation of the piperidine-1-carbothioamide fragment, and to compare the crystallographic results with those of molecular mechanics . Conformational analysis on the free-relating bonds of thioperamide w as performed with different search methods in order to find the minimu m-energy conformations and to estimate rotational barriers. For steric reasons, the rotation around the bond connecting the cyclohexane ring with the carbothioamide nitrogen is more hampered than that around th e bond connecting imidazole with piperidine. The rotation around the f irst bond presents two symmetrical energy minima separated from a thir d minimum by an energy barrier of 40 KJ/mol. The spatial disposition o f compound 1 in the crystal and the common part of thioperamide in one of its minimum-energy conformations are very similar. The minimum-ene rgy conformations of thioperamide calculated by molecular mechanics ar e therefore reliable and they can be used for structural comparisons w ith other H-3-receptor antagonists.