Sintesi e valutazione biologica di carbossammidi pirazoliche tricicliche contenenti cicloalchili quali nuovi ligandi cannabinergici

Cannabinoid receptor ligands are potential candidates for the therapy of chronic pain, neuroinflammatory diseases, cancer and obesity. In preceding studies the relevance and structure-activity relationships (SAR) of pyrazole derivatives have been consolidated and clarified, and in the process three series of tricyclic compounds as 1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazoles, 4,5-dihydro-1H-benzo[g]indazoles and 1,4-dihydroindeno[1,2-c]pyrazoles emerged as potent cannabinoid receptor ligands. In the present study five new series of 1,4-dihydroindeno[1,2-c]pyrazole and 1H-benzo[g]indazole carboxamides containing a cyclopropyl, cyclopentyl or cycloexyl substituent were designed and synthesized to evaluate their affinities towards CB1 and CB2 receptors. Among these derivatives, compound 38Am, exibits a high affinity for CB2 receptor (Ki = 4.48nM) together with remarkable selectivity (KiCB1/KiCB1= 2232). It is interesting to note, in ain vitroneuroinflammatory test, that compound 3Am shows antagonist activity. Unexpectedly, compound 38Aa possess a agonistic biological profile.