Assessment of relative efficacies of 5-HT1A receptor ligands by means of in vivo animal models.
Assessment of relative efficacies of 5-HT1A receptor ligands by means of in vivo animal models.
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通过体内动物模型评估 5-HT1A 受体配体的相对功效。
DOI：
10.1016/s0014-2999(96)00621-8
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发表时间：
1996
影响因子：
5
通讯作者：
E. Moltzen
中科院分区：
文献类型：
--
作者：
C. Sánchez;J. Arnt;E. Moltzen
我们在反映突触前和/或突触后 5-HT1A 受体激活的三个体内模型中评估了具有不同功效的配体对 β-肾上腺素受体和 5-HT1A 受体的影响。大鼠前爪踩踏是由突触后 5-HT1A 受体介导的，8-OH-DPAT（8-羟基-2-（二正丙胺）四氢萘）诱导的辨别刺激主要由突触后介导，但也可能涉及突触前 5-HT1A 受体，足部电击诱导的超声发声主要涉及突触前 5-HT1A 受体。体外受体结合研究表明，(−)-喷布洛尔具有高 β-肾上腺素受体和 5-HT1A 受体亲和力，(+)-喷布洛尔具有高 β-肾上腺素受体和 60 倍低的 5-HT1A 受体亲和力，吲哚洛尔和 (−)-特他洛尔具有高 β-肾上腺素受体亲和力，而 5-HT1A 受体亲和力低约 100 倍，仅对美托洛尔和 ICI 118,551 的 β-肾上腺素受体（赤式-d,l-1-(7-甲基茚满-4-基氧基)-3-异丙胺-丁-2-醇，仅对 WAY 100.635 的 5-HT1A 受体有亲和力((N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺)。(−)-喷丁洛尔、(−)-特他洛尔、吲哚洛尔和WAY 100.635拮抗5-MeODMT诱导的(5-甲氧基-N,N-二甲基色胺)大鼠前爪踩踏，以及(+)-喷布洛尔、ICI 118,551 和美托洛尔无活性。(−)-喷布洛尔、WAY 100.635 和 (−)-特他洛尔拮抗大鼠中 8-OH-DPAT 诱导的辨别刺激，吲哚洛尔和美托洛尔在大鼠中表现出混合的拮抗和激动作用。在大鼠中，特他洛尔抑制最大 36%，WAY 100.635，(−)-喷布洛尔、(+)-喷布洛尔、美托洛尔和 ICI 118,551 无活性，(−)-喷布洛尔和 WAY 100.635 完全逆转 8-OH-DPAT 诱导的超声发声抑制，(−)-特他洛尔逆转最大抑制。 52% 和 (+)-喷丁洛尔和吲哚洛尔无活性。得出的结论是，可以通过应用一系列不同程度地涉及突触后和突触前受体的体内测试模型来估计 5-HT1A 受体的功效。5-HT1A 受体的体内功效排序为：WAY 100.635 = (-)-喷丁洛尔 < (-)-特他洛尔。 < 吲哚洛尔。
We have evaluated the effects of ligands with varying efficacies at β-adrenoceptors and 5-HT1Areceptors in three in vivo models reflecting pre- and/or postsynaptic 5-HT1Areceptor activation. Forepaw treading in rats is mediated by postsynaptic 5-HT1Areceptors, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamin)tetralin)-induced discriminative stimulus is predominantly mediated by postsynaptic, but presynaptic 5-HT1Areceptors might also be involved, and footshock-induced ultrasonic vocalization involves predominantly presynaptic 5-HT1Areceptors. In vitro receptor binding studies demonstrated high β-adrenoceptor and 5-HT1Areceptor affinity of (−)-penbutolol, high β-adrenoceptor and 60 times lower 5-HT1Areceptor affinity of (+)-penbutolol, high β-adrenoceptor affinity and about 100 times lower 5-HT1Areceptor affinity of pindolol and (−)-tertatolol, only affinity for β-adrenoceptors of metoprolol and ICI 118,551 (erythro-d,l-1-(7-methylindan-4-yloxy)-3-isopropylamine-butan-2-ol, and only affinity for 5-HT1Areceptors of WAY 100.635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexane-carboxamide). (−)-Penbutolol, (−)-tertatolol, pindolol and WAY 100.635 antagonized 5-MeODMT-induced (5-methoxy-N,N-dimethyltryptamine) forepaw treading in rats, and (+)-penbutolol, ICI 118,551 and metoprolol were inactive. (−)-Penbutolol, WAY 100.635 and (−)-tertatolol antagonized 8-OH-DPAT-induced discriminative stimulus in rats, pindolol and metoprolol showed a mixed antagonistic and agonistic profile. Pindolol antagonized footshock-induced ultrasonic vocalization in rats, tertatolol inhibited maximum 36% and WAY 100.635, (−)-penbutolol, (+)-penbutolol, metoprolol and ICI 118,551 were inactive. (−)-Penbutolol and WAY 100.635 reversed 8-OH-DPAT-induced inhibition of ultrasonic vocalization completely, (−)-tertatolol reversed maximum 52% and (+)-penbutolol and pindolol were inactive. It is concluded, that efficacies at 5-HT1Areceptors can be estimated by applying a battery of in vivo test models that involve post- and presynaptic receptors to a variable degree. The in vivo ranking order of efficacy at 5-HT1Areceptors was: WAY 100.635 = (−)-penbutolol < (−)-tertatolol < pindolol.