Kidd E J, Haj-Dahmane S, Jolas T, Lanfumey L, Fattaccini C M, Guardiola-Lemaitre B, Gozlan H, Hamon M
INSERM U288, Neurobiologie Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, Paris, France.
J Pharmacol Exp Ther. 1993 Feb;264(2):863-72.
The potential interaction of the new methoxy-chroman derivatives: (+/-)-S 20244 (4-[N-(5-methoxy-chroman-3-yl)N-propylamino]butyl-8-azaspiro- (4,5)-decane-7,9-dione) and its enantiomers (+)-S 20499 and (-)-S 20500 with central 5-hydroxytryptamine1A (5-HT1A) receptors was assessed using biochemical and electrophysiological tests in the rat. In vitro binding assays revealed that these drugs bound with high affinity to 5-HT1A sites in hippocampal membranes (Ki: 0.19 nM for (+)-S 20499, 0.95 nM for (-)-S 20500 and 0.35 nM for the racemate (+/-) S 20244). As seen with the prototypical 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin, (+/-)-S 20244, (+)-S 20499 and (-)-S 20500 inhibited forskolin-activated adenylate cyclase in hippocampal homogenates with potencies corresponding to their respective affinities for 5-HT1A sites. The maximal inhibitory effect of the chroman derivatives was not additive with that of 8-hydroxy-2-(di-n- propylamino)tetralin and could be competitively reduced by 5-HT1A antagonists such as (-)-propranolol and (+/-)-tertatolol. Electrophysiological recordings within the dorsal raphe nucleus both in vitro (in brain-stem slices) and in vivo (in chloral hydrate anesthetized rats) showed that (+)-S 20499, (+/-)-S 20244 and (-)-S 20500 induced, in that order of (decreasing) potency, a dose-dependent reduction in the spontaneous firing of serotoninergic neurons. In vitro, as well as in vivo, the inhibitory influence of the chroman derivatives on the discharge frequency of serotoninergic neurons could be competitively antagonized by (+/-)-tertatolol. Finally, oral administration of increasing doses of the most potent enantiomer, (+)-S 20499, induced a marked reduction in the rate of 5-HT turnover, without affecting that of dopamine, in various brain areas. All these biochemical and electrophysiological data indicate that (+)-S 20499 is a highly potent agonist at both presynaptic (i.e., somatodendritic) and postsynaptic 5-HT1A receptors in the rat brain.
使用大鼠进行生化和电生理测试，评估了新型甲氧基色满衍生物：（±）-S 20244（4-[N-（5-甲氧基色满-3-基）N-丙基氨基]丁基-8-氮杂螺（4,5）-癸烷-7,9-二酮）及其对映体（+）-S 20499和（-）-S 20500与中枢5-羟色胺1A（5-HT1A）受体的潜在相互作用。体外结合试验表明，这些药物与海马膜中的5-HT1A位点具有高亲和力结合（Ki：（+）-S 20499为0.19 nM，（-）-S 20500为0.95 nM，外消旋体（±）S 20244为0.35 nM）。如原型5-HT1A激动剂8-羟基-2-（二正丙基氨基）四氢萘所见，（±）-S 20244、（+）-S 20499和（-）-S 20500抑制海马匀浆中福斯高林激活的腺苷酸环化酶，其效力与其对5-HT1A位点的各自亲和力相对应。色满衍生物的最大抑制作用与8-羟基-2-（二正丙基氨基）四氢萘的最大抑制作用不是相加的，并且可以被5-HT1A拮抗剂如（-）-普萘洛尔和（±）-特他洛尔竞争性降低。体外（在脑干切片中）和体内（在水合氯醛麻醉的大鼠中）背缝核内的电生理记录表明，（+）-S 20499、（±）-S 20244和（-）-S 20500按（递减）效力顺序诱导5-羟色胺能神经元自发放电的剂量依赖性降低。在体外以及体内，色满衍生物对5-羟色胺能神经元放电频率的抑制作用可被（±）-特他洛尔竞争性拮抗。最后，口服递增剂量的最有效对映体（+）-S 20499，在各个脑区诱导5-羟色胺周转率显著降低，而不影响多巴胺的周转率。所有这些生化和电生理数据表明，（+）-S 20499是大鼠脑中突触前（即体树突）和突触后5-HT1A受体的高效激动剂。
