Roberts C, Price G W, Gaster L, Jones B J, Middlemiss D N, Routledge C
Department of Psychiatry Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, U.K.
Neuropharmacology. 1997 Apr-May;36(4-5):549-57. doi: 10.1016/s0028-3908(97)00026-9.
The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.
利用选择性5-羟色胺（5-HT）1B受体配体SB 219085、SB 220272、SB 224289和SB 216641，研究了5-HT1B受体选择性对5-HT终末自身受体活性的重要性。这些研究采用了体外化合物亲和力和效能的测量，以及使用体内微透析法对自由活动豚鼠额叶皮质细胞外5-HT的测量。所有化合物对5-HT1B受体都具有高亲和力和选择性，其中SB 224289对5-HT1B受体的选择性高于5-HT1D受体。这些化合物在两种受体上均表现出一系列效能：SB 224289和SB 219085为反向激动剂，SB 220272为拮抗剂，SB 216641为部分激动剂。全身给药后，SB 220272、SB 216641和SB 224289对细胞外5-HT没有影响，然而，SB 219085却使其显著增加。SB 219085引起的细胞外5-HT增加归因于该化合物的非特异性释放特性，因为它还被证明能增加预先加载的豚鼠皮质切片中[3H]5-HT的基础释放。上述5-HT1B受体选择性化合物缺乏作用，以及非选择性化合物GR 127935、GR125743和甲硫噻平引起的细胞外5-HT降低，表明5-HT1D受体的拮抗作用可能介导了5-HT水平的这种降低。5-HT1D受体的阻断增加中缝核中的5-HT水平，这激活了5-HT1A受体，导致终末5-HT释放总体减少，这似乎是合理的。现在，确凿的证据有待于对选择性5-HT1D受体拮抗剂作用的阐明。
