Gacel G, Zajac J M, Delay-Goyet P, Daugé V, Roques B P
Département de Chimie Organique, U 266 INSERM, UA 498 CNRS, Faculté de Pharmacie, Paris, France.
J Med Chem. 1988 Feb;31(2):374-83. doi: 10.1021/jm00397a019.
The previous rules proposed for selective recognition of mu and delta opioid receptors by modified enkephalins were investigated through an extensive structure-activity study. Thus, modifications of the sequence of TRIMU 4 (Tyr-D-Ala-Gly-NHCH(CH3)CH2CH(CH3)2, a peptide that exhibits mu selectivity close to that of DAGO (Try-D-Ala-Gly-N(Me)Phe-Gly.ol), were performed for two positions, 2 and 4, critical for mu recognition. The drastic loss of potency following introduction of L-Ala or Aib in position 2 emphasizes the importance of the stereochemistry and the steric size of the X2 amino acid for optimal mu binding. The enhancement of the intrinsic flexibility of the C-terminal alkyl chain of TRIMU 4 through removal of a methyl group leads to TRIMU 5 (Tyr-D-Ala-Gly-NHCH2CH2CH(CH3)2), a peptide with a mu selectivity similar to that of DAGO. In contrast, introduction of an O-tert-butyl Ser2 residue increases affinity for delta receptors. In the hexapeptide series derived from DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr), a D-Thr2 moiety was shown to be very efficient in improving delta recognition and delta selectivity appeared also to be modulated by the nature of the sixth residue. The potencies of the 24 peptides studied to inhibit the electrically evoked contractions of the GPI or MVD are relatively well correlated with their affinities for brain mu or delta receptors labeled with [3H]DAGO or [3H]DSLET, respectively. Moreover, the analgesic potency (hot plate test) of the peptides is related to their affinity for rat brain mu receptors. The wide range of receptor affinities exhibited by the compounds reported here could be useful to study the physiological role of mu and delta receptors.
通过广泛的构效关系研究，对先前提出的经修饰脑啡肽选择性识别μ和δ阿片受体的规则进行了研究。因此，对TRIMU 4（Tyr-D-Ala-Gly-NHCH(CH3)CH2CH(CH3)2，一种表现出与DAGO（Try-D-Ala-Gly-N(Me)Phe-Gly.ol）相近的μ选择性的肽）的序列进行了修饰，修饰位点为对μ识别至关重要的第2位和第4位。在第2位引入L-Ala或Aib后活性急剧丧失，这强调了X2氨基酸的立体化学和空间大小对最佳μ结合的重要性。通过去除一个甲基增强TRIMU 4 C末端烷基链的内在柔韧性，得到了TRIMU 5（Tyr-D-Ala-Gly-NHCH2CH2CH(CH3)2），一种具有与DAGO相似的μ选择性的肽。相反，引入O-叔丁基Ser2残基会增加对δ受体的亲和力。在源自DSLET（Tyr-D-Ser-Gly-Phe-Leu-Thr）的六肽系列中，D-Thr2部分在改善δ识别方面非常有效，并且δ选择性似乎也受第6位残基性质的调节。所研究的24种肽抑制GPI或MVD电诱发收缩的活性与其对分别用[3H]DAGO或[3H]DSLET标记的脑μ或δ受体的亲和力相对较好地相关。此外，这些肽的镇痛活性（热板试验）与其对大鼠脑μ受体的亲和力有关。本文报道的化合物所表现出的广泛受体亲和力可能有助于研究μ和δ受体的生理作用。
