Manera Clementina, Saccomanni Giuseppe, Adinolfi Barbara, Benetti Veronica, Ligresti Alessia, Cascio Maria Grazia, Tuccinardi Tiziano, Lucchesi Valentina, Martinelli Adriano, Nieri Paola, Masini Emanuela, Di Marzo Vincenzo, Ferrarini Pier Luigi
Dipartimento di Scienze Farmaceutiche, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
J Med Chem. 2009 Jun 25;52(12):3644-51. doi: 10.1021/jm801563d.
The CB(2) receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives, new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the human CB(1) and CB(2) cannabinoid receptors. Some of the reported compounds showed a subnanomolar CB(2) affinity with a CB(1)/CB(2) selectivity ratio greater than 200 (compounds 6, 12, cis-12, 13, and cis-13). Further studies revealed that compound 12, which presented benzyl and carboxy-4-methylcyclohexylamide substituents bound in the 1 and 3 positions, exerted a CB(2)-mediated inhibitory action on immunological human basophil activation. On the human T cell leukemia line Jurkat the same derivative induced a concentration-dependent decrease of cell viability. The obtained results suggest that 1,8-naphthyridin-2(1H)-on-3-carboxamides represent a new scaffold very suitable for the development of new promising CB(2) agonists.
CB(2)受体激活可用于治疗慢性疼痛和免疫源性肿瘤等疾病，且无精神活性。基于我们已报道的1,8-萘啶-4(1H)-酮-3-甲酰胺衍生物，设计、合成了新的1,8-萘啶-2(1H)-酮-3-甲酰胺衍生物，并测试了它们对人CB(1)和CB(2)大麻素受体的亲和力。一些报道的化合物表现出亚纳摩尔级的CB(2)亲和力，CB(1)/CB(2)选择性比大于200（化合物6、12、顺式-12、13和顺式-13）。进一步研究表明，在1和3位带有苄基和羧基-4-甲基环己基酰胺取代基的化合物12，对人嗜碱性粒细胞激活具有CB(2)介导的抑制作用。在人T细胞白血病细胞系Jurkat上，相同的衍生物诱导细胞活力呈浓度依赖性下降。所得结果表明，1,8-萘啶-2(1H)-酮-3-甲酰胺代表一种非常适合开发新的有前景的CB(2)激动剂的新骨架。
