NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

Deltorphins（DEL A、B或C）是一种高度选择性的阿片肽， 用作大脑阿片受体的分子和化学探针。 受体 使用外周组织的结合分析和药理学测定 能够描绘特定的分子特性， 激动剂/拮抗剂相互作用。 DEL的关键分子特征基于 对180多个合成类似物的研究：（1）D-Try 1，N-延伸的TRY 1 或DEL C中的桥连[TRY 1-Asp 4]对于结合是不可接受的。 (2)一 在位置5处需要具有疏水侧链的残基，尽管 结合受C-末端四肽中序列的影响; 序列的反转导致选择性的反转（-）。 （三） 被卤素、氨基或硝基取代 Phe 3修饰脑受体选择性和生物活性;而 [p-BrPhe 3]的受体选择性是DEL C、[p-ClPhe 3]和 通过生物测定（MVD），[p-BrPhe 3]比DEL C高近4倍和2倍， 然而，生物活性效力和受体之间的唯一相关性 与受体发生结合。 (4)修改电子， 在DEL C中Phe 3的疏水性和构象性质通过 使用5和6元环和双环结构。 总的来说这些 取代对于亲和力和选择性是有害的，然而，Aic 3 Atc（R，S）3增强了亲和性，而Atc（R，S）3也增加了选择性。 (5)[D-Asp 4]-、[Pro4]-或[Abu 4]DEL C轻微影响的亲和力： 前两个类似物定义了一个双位点结合模型，而DEL C和 [Abu 4] DEL C为单部位模型。 [NaMe Phe 3]-和[Atc（S）3] DEL C 揭示出，分子能量构象似乎预测实验 衍生的亲和力。 分子动力学计算表明， 其他的低能构型可以描述它们的构象 在受体相互作用过程中;假环化涉及的残基在 位置3和4或被双环结构Atc 3取代可 代表最理想的溶液构象异构体。

Deltorphins (DEL A,B, or C), highly selective opioid heptapetides, were used as molecular and chemical probes for brain opioid receptors. Receptor binding analyses and pharmacological assays using peripheral tissues enabled a delineation of specific molecular properties for agonist/antangonist interactions. Key molecular features of DEL were based on the study of over 180 synthetic analogues: (1) D-Try1,an N-extended TRY1 or a bridged [TRY1-Asp4] in DEL C are unacceptable for binding. (2) A residue with a hydrophobic side-chain is required at position 5, although binding is affected by the sequence in the C-terminal tetrapeptide; inversion of sequence brought about a reversal in selectivity (- ). (3) Substitution by halogens, amino or nitro groups at the para-position of Phe3 modified brain receptor selectivity and bioactivity; whereas [p-BrPhe3] exhibited twice receptor selectivity as DEL C, [p-ClPhe3] and [p-BrPhe3] were nearly 4- and 2-fold higher than DEL C by bioassay (MVD), however, the only correlation between bioactive potency and receptor binding occured with recptors. (4) Modification of the electronic, hydrophobic and conformational properties of Phe3 in DEL C occurred through use of 5 and 6 membered rings and bicyclic structures. In general, these substitutions were deleterious for affinity and selectivity, however, Aic3 and Atc(R,S)3 enhanced affinity; the latter increased selectivity as well. (5) [D-Asp4]-, [Pro4]- or [Abu4]DEL C slighty affected affinities: the former two analogues defined a two-site binding model, while DEL C and [Abu4] DEL C were one-site models. [NaMe Phe 3]- and [Atc(S)3] DEL C revealed that the mimal energy conformer appeared to predict experimentally derived affinities. Futhermore, molecular dynamics calculations implied that the other low energy configurations could describe their conformation during receptor interactions; pseudo-cyclization involving the residues at positions 3 and 4 or replacement by the bicyclic ring structure Atc3 may represent the most desirable solution conformer.