Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces δ-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference.
Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces δ-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference.
复制标题
DOI：
10.3390/ph16091218
复制
发表时间：
2023-08-29
期刊：
影响因子：
--
通讯作者：
Aldrich JV
中科院分区：
文献类型：
--
作者：
Scherrer KH;Eans SO;Medina JM;Senadheera SN;Khaliq T;Murray TF;McLaughlin JP;Aldrich JV
大环四肽j - 15208 （cyclo[ph - d - pro - ph - trp]）及其D-Trp异构体表现出kappa阿片受体（KOR）拮抗作用，可防止应激诱导的消失的可卡因条件下的位置偏好恢复。在这里，我们评估了取代色氨酸和d -色氨酸对肽的阿片活性、抗痛感耐受性和防止复发的能力的影响。采用固相多肽合成和溶液环化相结合的方法合成了6个类似物。在体外，通过放射性配体竞争结合实验评估了这些类似物对阿片受体的亲和力，在[35S]GTPγS实验中评估了它们的有效性，在小鼠肝微粒体中评估了它们的代谢稳定性，在小鼠55°C温水脱尾实验中评估了它们在体内的阿片活性和选择性。在体内评估了运动障碍、呼吸抑制、急性耐受性和条件位置偏好（CPP）的潜在责任，并评估了类似物对消失的可卡因-位置偏好恢复的改善作用。其他d -氨基酸取代D-Trp不影响（或在一个案例中增加）KOR亲和力，而三个l -氨基酸取代Trp中的两个降低了KOR亲和力。相比之下，除一种替代外，所有替代都增加了mu阿片受体（MOR）的体外亲和力。这些类似物的代谢稳定性与它们各自的母体肽相似，含有d -氨基酸的类似物比在该位置含有l -氨基酸的类似物代谢得更快。在体内，cj - 15208类似物显示出抗痛觉性，尽管其效力在80倍范围内变化，并且介导的阿片受体因取代而不同。除了d -苯并噻吩丙氨酸类似物外，所有类似物都失去了KOR拮抗作用，而2 ' -萘丙氨酸类似物反而表现出显著的δ阿片受体（DOR）拮抗作用。DOR拮抗剂的引入同时降低了急性阿片类药物抗痛觉性耐受性，并防止应激诱导的消失的可卡因- cpp的恢复。
The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [35S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP.
登录
查看更多内容
影响因子：
--
作者：
Aceto MD;Harris LS;Negus SS;Banks ML;Hughes LD;Akgün E;Portoghese PS
通讯作者：
Portoghese PS
影响因子：
3.4
作者：
Nielsen CK;Simms JA;Bito-Onon JJ;Li R;Ananthan S;Bartlett SE
通讯作者：
Bartlett SE
影响因子：
2.7
作者：
Bender, Aaron M.;Clark, Mary J.;Mosberg, Henry I.
通讯作者：
Mosberg, Henry I.
影响因子：
3.4
作者：
DEVRIES, TJ;BABOVICVUKSANOVIC, D;SHIPPENBERG, TS
通讯作者：
SHIPPENBERG, TS
影响因子：
13.5
作者：
Chung, Paul Chu Sin;Kieffer, Brigitte L.
通讯作者：
Kieffer, Brigitte L.