Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors

Cannabinoid receptors have been studied extensively in view of their potential functional role in several physiological and pathological processes. For this reason, the search for new potent, selective ligands for subtype CB receptors, CB1 and CB2, is still of great importance, in order to investigate their role in various physiological functions. The present study describes the synthesis and the biological properties of a series of 1,8-naphthyridine derivatives, characterised by the presence of some important structural requirements exhibited by other classes of cannabinoid ligands, such as an aliphatic or aromatic carboxamide group in position 3, and an alkyl or arylalkyl substituent in position 1. These compounds were assayed for binding both to the brain and to peripheral cannabinoid receptors (CB1 and CB2). The results obtained indicate that the naphthyridine derivatives examined possess a greater affinity for the CB2 receptor than for the CB1 receptor. In particular, derivatives 6a and 7a possess an appreciable affinity for the CB2 receptor, with K-i values of 5.5 and 8.0 nM respectively; also compounds 4a, Sa and 8a exhibit a good CB2 affinity, with Ki values in the range of 10-44 nM. Furthermore, compounds 3g-i and 18 revealed a good CB2 selectivity, with a CB1/CB2 ratio > 20. (C) 2004 Elsevier Ltd. All rights reserved.