10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed kappa and micro opioid ligands: synthesis and biological evaluation of their binding affinity at opioid receptors.
10-Ketomorphinan and 3-substituted-3-desoxymorphinan analogues as mixed kappa and micro opioid ligands: synthesis and biological evaluation of their binding affinity at opioid receptors.
复制标题
10-酮吗啡喃和 3-取代-3-脱氧吗啡喃类似物作为混合 kappa 和微阿片配体：其与阿片受体的结合亲和力的合成和生物学评价。
DOI：
10.1021/jm0304156
复制
发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Neumeyer,JohnL
中科院分区：
文献类型：
--
作者：
Zhang,Ao;Xiong,Wennan;Bidlack,JeanM;Hilbert,JamesE;Knapp,BrianI;Wentland,MarkP;Neumeyer,JohnL
A series of 10-ketomorphinan analogues were synthesized, and their binding affinity at all three opioid receptors was investigated. In most cases, high affinity at μ and κ receptors, and lower affinity at δ receptor was observed, resulting in good selectivity for μ and κ receptors. A wide range of substituents can be accommodated on the nitrogen position. TheN-(S)-tetrahydrofurfuryl analogue11displayed the highest affinity at all three receptors. TheN-cyclobutylmethyl analogue13gave both high affinity and selectivity at κ receptor, andN-2-phenylethyl analogue18exhibited good affinity and selectivity at μ receptor. Further modifications of the 3-substituent indicated that one H-bond donor was an essential requirement for good affinity at μ and κ receptors. Similar modifications were investigated at the 3-OH group of morphinans: levorphanol (2a), cyclorphan (2b), and MCL-101 (2c) lacking the 10-keto group. The 3-amino bioisosteric analogues (40and41) displayed reasonably good affinity at μ and κ receptors. The 3-carboxamido replacement (compounds46−48) in the morphinan subseries resulted in similar affinities comparable to their corresponding 3-OH congeners. The high affinity of these carboxamido analogues, along with their greater lipophilicity and metabolic stability, make them promising candidates for further pharmacological investigation.
