Potent δ-opioid receptor agonists containing the Dmt-Tic pharmacophore
Potent δ-opioid receptor agonists containing the Dmt-Tic pharmacophore
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DOI：
10.1021/jm020336e
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发表时间：
2002-12-05
影响因子：
7.3
通讯作者：
Lazarus, LH
中科院分区：
文献类型：
--
作者：
Balboni, G;Salvadori, S;Lazarus, LH
将含有2 ′，6 ′-二甲基-L-酪氨酸（Dmt）-1，2，3，4-四氢异喹啉-3-羧酸（Tic）药效团的δ-阿片受体拮抗剂转化为有效的δ-激动剂需要第三个杂芳核，如1H-苯并咪唑-2-基（Bid）和特定长度的接头，两者都位于通式H-Dmt-Tic-NH-CH（R）-R ′中Tic的C-末端。Tic和Bid之间的距离是负责获得δ激动作用（2，2 '，3，4，6）或δ拮抗作用（8）的决定因素。含有C-末端Ala（1，1 '）、Asp（5）或Asn（7）与酰胺（1，1'，5）或游离酸基团（7）的化合物用作缺乏第三个杂芳环的δ-拮抗剂对照。间隔区（2，2 '）的手性变化或通过Asp衍生物（4，6）包含负电荷导致了强效的Delta激动作用和中度激动作用，尽管Delta受体亲和力对于4下降了约10倍，而μ亲和力下降了超过2个数量级。连接体中负电荷的重新定位改变了活性：H-Dmt-Tic-NH-CH（CH 2-Bid）COOH（6）保持高δ亲和力（Ki = 0.042 nM）和δ激动作用（IC 50 = 0.015 nM），但游离酸基团与Bid [H-Dmt-Tic-NH-CH 2-Bid（CH 2-COOH）（9）]的连接重建了δ拮抗作用（Ki = 0.27 nM）。数据表明，将Dmt-Tic药效团和Bid分开的接头，无论是否存在负电荷，在从母体δ拮抗剂获得表现出有效δ激动作用和弱激动作用的阿片类药物中是重要的。
Conversion of delta-opioid receptor antagonists containing the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent delta-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NH-CH(R)-R'. The distance between Tic and Bid is a determining factor responsible for the acquisition of delta agonism (2, 2', 3, 4, 6) or delta antagonism (8). Compounds containing a C-terminal Ala (1, 1'), Asp (5), or Asn (7) with an amide (1, 1', 5) or free acid group (7) served as delta-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2') or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent delta agonism and moderatey agonism, although delta-receptor affinity decreased about 10-fold for 4 while mu affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH2-Bid)COOH (6) maintained high delta affinity (K-i = 0.042 nM) and delta agonism (IC50 = 0.015 nM), but attachment of the free acid group to Bid [H-Dmt-Tic-NH-CH2-Bid(CH2-COOH) (9)] reconstituted delta antagonism (K-e = 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent delta agonism and weaky agonism from a parent delta antagonist.