Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Sassari, Italy.
KemoTech Srl, Pula, CA, Italy.
Chem Biol Drug Des. 2018 Jan;91(1):181-193. doi: 10.1111/cbdd.13069. Epub 2017 Jul 29.
Novel 1,4-dihydropyrazolo[3,4-a]pyrrolizine-, 4,5-dihydro-1H-pyrazolo[4,3-g]indolizine- and 1,4,5,6-tetrahydropyrazolo[3,4-c]pyrrolo[1,2-a]azepine-3-carboxamide-based compounds were designed and synthesized for cannabinoid CB and CB receptor interactions. Any of the new synthesized compounds showed high affinity for CB receptor with K values superior to 314 nm, whereas some of them showed moderate affinity for CB receptor with K values inferior to 400 nm. 7-Chloro-1-(2,4-dichlorophenyl)-N-(homopiperidin-1-yl)-4,5-dihydro-1H-pyrazolo[4,3-g]indolizine-3-carboxamide (2j) exhibited good affinity for CB receptor (K CB = 81 nm) and the highest CB /CB selectively ratio (>12). Docking studies carried out on such compounds were performed using the hCB X-ray in complex with the close pyrazole analogue AM6538 and disclosed specific pattern of interactions related to the tricyclic pyrrolopyrazole scaffolds as CB ligands.
新型 1,4-二氢吡唑并[3,4-a]吡咯嗪、4,5-二氢-1H-吡唑并[4,3-g]吲哚嗪和 1,4,5,6-四氢吡唑并[3,4-c]吡咯并[1,2-a]氮杂卓-3-甲酰胺类化合物被设计和合成，用于研究大麻素 CB 和 CB 受体相互作用。任何新合成的化合物对 CB 受体均表现出高亲和力，K i 值均优于 314nm，而其中一些化合物对 CB 受体表现出中等亲和力，K i 值均低于 400nm。7-氯-1-(2,4-二氯苯基)-N-(高哌啶-1-基)-4,5-二氢-1H-吡唑并[4,3-g]吲哚嗪-3-甲酰胺（2j）对 CB 受体表现出良好的亲和力（K CB = 81nm）和最高的 CB / CB 选择性比值（>12）。对这些化合物进行的对接研究使用与近吡唑类似物 AM6538 结合的 hCB X 射线复合物进行，揭示了与三环吡咯并吡唑骨架作为 CB 配体相关的特定相互作用模式。
