Tóth G, Darula Z, Péter A, Fülöp F, Tourwé D, Jaspers H, Verheyden P, Böcskey Z, Tóth Z, Borsodi A
Isotope Laboratory and Institute of Biochemistry, Hungarian Academy of Sciences, Szeged, Hungary.
J Med Chem. 1997 Mar 14;40(6):990-5. doi: 10.1021/jm9602726.
Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorpin analogs with altered hydrophobic and stereoelectronic properties. Deltorphin I and II analogs were synthesized involving the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 2-aminotetralin-2-carboxylic acid (Atc) instead of Phe in the message domain. The peptides were agonists in the subnanomolar range in the MVD assay and in the micromolar or higher range in the GPI assay, showing a very high selectivity for delta receptors. A very similar trend could be observed in radioreceptor binding assays in which selective tritiated opioid ligands were used. (R)- and (S)-Atc-deltoriphins exhibited similar Ki values in the binding assay, with almost complete loss of the stereospecificity of the binding. Conformational studies provided evidence for the little disturbance of the backbone conformational equilibrium when Phe3 is replaced by (S)- or (R)-Atc. The use of the Atc constraint gives additional evidence that, during its interaction with the delta receptor, the side chain of residue 3 adopts the trans conformation at chi 1.
采用两种设计极具活性和高选择性δ阿片肽的方法来获得具有改变的疏水和立体电子性质的新型强啡肽类似物。合成了强啡肽I和II类似物，其中在识别结构域的第5和6位用异亮氨酸取代缬氨酸，在信息结构域用2-氨基四氢萘-2-羧酸（Atc）取代苯丙氨酸。这些肽在MVD试验中为亚纳摩尔范围内的激动剂，在GPI试验中为微摩尔或更高范围内的激动剂，对δ受体表现出非常高的选择性。在使用选择性氚化阿片配体的放射受体结合试验中也可观察到非常相似的趋势。（R）-和（S）-Atc-强啡肽在结合试验中表现出相似的Ki值，结合的立体特异性几乎完全丧失。构象研究提供了证据，表明当苯丙氨酸3被（S）-或（R）-Atc取代时，主链构象平衡几乎没有受到干扰。使用Atc约束进一步证明，在其与δ受体相互作用期间，残基3的侧链在χ1处采取反式构象。
