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DEBORAH L. HEYL SHARON J. SCHMITTER HASSIBA BOUZIT THOMAS W. JOHNSON ANGELA M. HEPP KATHLEEN R. KURTZ CAROL MOUSIGIAN 《Chemical biology & drug design》1994,44(5):420-426
Deltorphins I and II (Tyr-D-Ala-Phe-Asp-Val-Val-Gly NH2 and Tyr-D-Ala-Phe-Glu-Val-Val-Gly NH2) display a high degree of 6-opioid receptor selectivity. Since they lack the intervening Gly3 residue found between the Tyr and Phe aromatic moieties in pentapeptide enkephalins, deltorphins I and II resemble a previously described series of cyclic tetrapep-tides based on Tyr-c[D-Cys-Phe-D-Pen] (JOM-13). With the goal of development of structure-activity relationships for deltorphins and comparison with that of the cyclic tetrapep-tides, ten analogs of deltorphin I were synthesized in which Phe3 was replaced with specific aromatic and nonaromatic amino acids with varying physicochemical properties. Results indicated that analogs containing the bicyclic aromatic amino acids 3-(l-naphthyl)-L-alanine [1-Nal; Ki(μ) = 767 nM, Ki(§) = 7.70 nM], 3-(2-naphthyl)-L-alanine [2-Nal; Ki(μ)= 1910 nM, Ki(§) = 49.2 nM], tryptophan [Ki(μ)= 1250 nM, Ki(§) = 23.9nM], and 3-(3-benzothienyl)-L-alanine [Bth; Ki(μ)= 112nM, Ki(§) = 3.36 nM] were fairly well tolerated at μ- and §-receptors, though affinity was compromised to varying degrees relative to deltorphin I. Shortening the Phe side chain by incorporation of phenylglycine (Pgl) was detrimental to both μ (Ki= 4710 nM) and § (Ki= 15.6 nM) binding, while extension of the side chain with homophenylalanine (Hfe) enhanced μ binding (Ki= 67.8 nM), leaving § affinity unaffected (Ki= 2.64 nM). Substitution with nonaromatic amino acids valine and isoleucine led expectedly to poor opioid binding [Ki(μ) =≥ 10000 nM for each, Ki(§) = 160 and 94.7 nM, respectively], while peptides containing cyclohexylalanine (Cha) and leucine surprisingly retained affinity at both μ (Ki= 322 and 1240 nM, respectively) and § (Ki= 10.5 and 12.4 nM, respectively) sites. In general, these trends mirror those observed for similar modification in Tyr-c[D-Cys-Phe-D-Pen]. 相似文献
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