Lawson J A, Cheng A, DeGraw J, Frenking G, Uyeno E, Toll L, Loew G H
SRI International, Menlo Park, California 94025.
J Med Chem. 1988 Oct;31(10):2015-21. doi: 10.1021/jm00118a028.
A series of 2-methyl-3-carbethoxy-3-(m-hydroxyphenyl)piperidine opiates (13a-d) with N-substituent variations have been synthesized, and their receptor affinities and in vivo agonist and antagonist activities and energy-conformational profiles have been determined. These are racemates of the alpha-epimer at the C-2 position, with a methyl group cis to the 3-phenyl group. One of the main goals of this study was to compare the conformational and pharmacological behavior of these 2-methyl "beta-meperidine" analogues to their 2-desmethyl racemic counterparts (14a-c) previously reported in the literature. The 2-desmethyl and 2-methyl analogues were found to have very similar phenyl equatorial conformers as their lowest energy forms with the addition of a 2-methyl group diminishing conformational flexibility. The presence of the 2-methyl group appears to diminish affinity at the mu-receptor and also to somewhat diminish already weak antinociceptic agonist activity. Given the similarity in lowest energy conformation, this reduction is most likely caused by the unfavorable interaction of the methyl group itself with a local mu-receptor binding site. Superposition of the phenol OH and protonated amine nitrogen NH of either 2-methyl enantiomer of 13a in its lowest energy conformer with the same OH and NH groups of metazocine, used as a high affinity rigid analogue, leads to reasonable overlap. However, the N-substituents and the piperidine and phenyl rings do not overlap in this proposed pharmacophore, perhaps accounting for the rather poor affinities found for these 3-phenylpiperidines and the lack of N-substituent modulation of affinity and efficacy as in fused ring opioids.
已合成了一系列具有不同N-取代基的2-甲基-3-乙氧羰基-3-(间羟基苯基)哌啶类阿片药物（13a - d），并测定了它们的受体亲和力、体内激动剂和拮抗剂活性以及能量构象分布。这些是C-2位α-差向异构体的外消旋体，甲基与3-苯基处于顺式。本研究的主要目标之一是比较这些2-甲基“β-哌替啶”类似物与其先前文献报道的2-去甲基外消旋对应物（14a - c）的构象和药理行为。发现2-去甲基和2-甲基类似物具有非常相似的苯基赤道构象作为其最低能量形式，2-甲基基团的加入降低了构象灵活性。2-甲基基团的存在似乎降低了对μ-受体的亲和力，也在一定程度上降低了本就较弱的抗伤害感受激动剂活性。鉴于最低能量构象的相似性，这种降低很可能是由于甲基本身与局部μ-受体结合位点的不利相互作用所致。将13a的最低能量构象中的2-甲基对映体的酚羟基OH和质子化胺氮NH与作为高亲和力刚性类似物的美他佐辛的相同OH和NH基团进行叠加，可得到合理的重叠。然而，在这个提议的药效团中，N-取代基以及哌啶环和苯环并不重叠，这可能解释了这些3-苯基哌啶的亲和力相当低，以及缺乏像稠环阿片类药物那样的N-取代基对亲和力和效力的调节作用。
