Novel Cyclic Biphalin Analogue with Improved Antinociceptive Properties

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• 作者：Adriano Mollica ; Alfonso Carotenuto ; Ettore Novellino ; Antonio Limatola ; Roberto Costante ; Francesco Pinnen ; Azzurra Stefanucci ; Stefano Pieretti ; Anna Borsodi ; Reza Samavati ; Ferenc Zador ; S谩ndor Benyhe ; Peg Davis ; Frank Porreca ; Victor J. Hruby
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：5
• 期：9
• 页码：1032-1036
• 全文大小：323K
• ISSN：1948-5875

文摘

Two novel opioid analogues have been designed by substituting the native d-Ala residues in position 2,2鈥?of biphalin with two residues of d-penicillamine or l-penicillamine and by forming a disulfide bond between the thiol groups. The so-obtained compound 9 containing d-penicillamines showed excellent 渭/未 mixed receptor affinities (K_i^未 = 5.2 nM; K_i^渭 = 1.9 nM), together with an efficacious capacity to trigger the second messenger and a very good in vivo antinociceptive activity, whereas product 10 was scarcely active. An explanation of the two different pharmacological behaviors of products 9 and 10 was found by studying their conformational properties.

Keywords:

Analgesics; biphalin; dimeric opioid peptides; cyclic analogues