Studies of the biochemical basis for the discriminative properties of 8-hydroxy-2-(di-n-propylamino)tetralin.
Studies of the biochemical basis for the discriminative properties of 8-hydroxy-2-(di-n-propylamino)tetralin.
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8-羟基-2-（二正丙氨基）四氢萘的生化基础研究。
DOI：
10.1016/0014-2999(93)90142-5
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发表时间：
1993
影响因子：
5
通讯作者：
Winter,JC
中科院分区：
文献类型：
--
作者：
Rabin,RA;Winter,JC
将一系列化合物模拟8-羟基-2-（二-正丙基氨基）四氢萘（8-OH-DPAT）的刺激特性的能力与以下进行比较：（1）这些化合物对5-HT 1A受体的亲和力;和（2）它们抑制毛喉素刺激的腺苷酸环化酶活性的功效。尽管对于九种化合物（氟辛克生、MDL 73005 EF、吉吡隆、伊沙匹隆、丁螺环酮、坦度螺酮、育亨宾、L 657，743和萝乌辛），完全交叉泛化与对5-HT 1A受体的高亲和力相关，但埃尔托拉嗪、d-麦角酸二乙酰胺和BMY 7378的pKD> 7.44，但没有表现出对8-OH-DPAT的完全模仿。此外，吲哚烯酸的pKD为7.88，但行为反应与生理盐水对照没有区别。由于上述数据表明对5-HT 1A受体的亲和力是必需的，但不足以使受体配体模拟8-OH-DPAT，因此通过测量海马膜中毛喉素刺激的腺苷酸环化酶活性的抑制来测定各种化合物对5-HT 1A受体的体外功效。对于一系列药物（吉哌隆、伊沙匹隆、flesinoxan、丁螺环酮、坦度螺酮、育亨宾、L 657，743和萝芙木碱），观察到对毛喉素刺激的腺苷酸环化酶活性的显著抑制，并且这些相同的药物显示出完全的交叉泛化。然而，BMY 14802和MDL 73005 EF没有改变腺苷酸环化酶的活性，但完全模仿8-OH-DPAT的刺激特性。Eltoprazine在抑制毛喉素刺激的腺苷酸环化酶活性方面具有显著疗效，但该药物给药后仅30%的反应在8-OH-DPAT适当水平。此外，虽然吲哚烯酸抑制海马腺苷酸环化酶的活性，该化合物的行为反应是从生理盐水对照没有区别。目前的研究表明，激活5-HT 1A受体的负耦合腺苷酸环化酶既不是必要的，也不足以受体ligandto模仿8-OH-DPAT的刺激特性。
The ability of a series of compounds to mimic the stimulus properties of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was compared to: (1) the affinity of these compounds for the 5-HT1Areceptor; and (2) their efficacy to inhibit forskolin-stimulated adenylate cyclase activity. Although for nine compounds (flesinoxan, MDL 73005EF, gepirone, ipsapirone, buspirone, tandospirone, yohimbine, L 657,743 and rauwolscine) complete cross generalization was associated with high affinity for the 5-HT1Areceptor, eltoprazine, d-lysergic acid diethylamide and BMY 7378 had pKD> 7.44, but did not show complete mimicry of 8-OH-DPAT. In addition, indorenate had a pKDof 7.88, yet the behavioral response was indistinguishable from the saline control. Because the above data indicated that affinity for the 5-HT1Areceptor was necessary, but not sufficient for a receptor ligand to mimic 8-OH-DPAT, the in vitro efficacy of the various compounds at the 5-HT1Areceptor was determined by measuring inhibition of forskolin-stimulated adenylate cyclase activity in hippocampal membranes. For a series of drugs (gepirone, ipsapirone, flesinoxan, buspirone, tandospirone, yohimbine, L 657,743 and rauwolscine) significant inhibition of forskolin-stimulated adenylate cyclase activity was observed, and these same drugs showed complete cross generalization. However, BMY 14802 and MDL 73005EF did not alter adenylate cyclase activity, yet completely mimicked the stimulus properties of 8-OH-DPAT. Eltoprazine had significant efficacy in inhibiting forskolin-stimulated adenylate cyclase activity, but only 30% of the responses following administration of this drug were on the 8-OH-DPAT-appropriate lever. Furthermore, although indorenate inhibited hippocampal adenylate cyclase activity, the behavioral response to this compound was indistinguishable from the saline control. The present study indicates that activation of the 5-HT1Areceptor negatively coupled to adenylate cyclase is neither necessary nor sufficient for a receptor ligandto mimic the stimulus properties of 8-OH-DPAT.