Hutchison A J, de Jesus R, Williams M, Simke J P, Neale R F, Jackson R H, Ambrose F, Barbaz B J, Sills M A
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
J Med Chem. 1989 Sep;32(9):2221-6. doi: 10.1021/jm00129a031.
A general synthetic approach to a novel series of cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols is described together with their receptor-binding profile on opioid-receptor subtypes (mu, kappa, delta). In addition, their in vivo antinociceptive activity was assessed. A number of the analogues synthesized showed potent affinity for opioid receptors and have potent antinociceptive activity in a mouse phenylquinone abdominal stretching model. In addition, the SAR for nitrogen substitution in the above series is explored with respect to the overall opioid receptor subtype binding profile. In general it was found that substituents which enhanced mu and kappa binding affinity in the benzomorphan series had a similar effect in the benzofuropyridine series described in this manuscript. An overlap hypothesis topologically connecting the benzomorphan nucleus to the cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine nucleus is also presented.
描述了一种合成一系列新型顺式-1,2,3,4,4a,9a-六氢苯并呋喃并[2,3-c]吡啶-6-醇的通用方法，以及它们对阿片受体亚型（μ、κ、δ）的受体结合特征。此外，还评估了它们的体内抗伤害感受活性。合成的许多类似物对阿片受体显示出强效亲和力，并在小鼠苯醌腹部伸展模型中具有强效抗伤害感受活性。此外，针对上述系列中氮取代的构效关系，研究了其对整体阿片受体亚型结合特征的影响。总体而言，发现在苯吗喃系列中增强μ和κ结合亲和力的取代基，在本手稿所述的苯并呋喃吡啶系列中具有类似作用。还提出了一种将苯吗喃核与顺式-1,2,3,4,4a,9a-六氢苯并呋喃并[2,3-c]吡啶核进行拓扑连接的重叠假说。
