De Vry J, Jentzsch K R
CNS Research, Bayer, Cologne, Germany.
Eur J Pharmacol. 1998 Sep 11;357(1):1-8. doi: 10.1016/s0014-2999(98)00503-2.
The aminomethylchroman derivative BAY x 3702 (R-(-)-2-¿4-[(chroman-2-ylmethyl)-amino]-butyl¿-1,1-dioxo-benzo[d] isothiazolone HCl) has recently been characterized as a relatively selective, high affinity 5-HT1A receptor agonist with neuroprotective, anxiolytic- and antidepressant-like effects in animal models. It was the aim of the present study to further confirm its receptor binding profile in an in vivo assay. Rats were trained to discriminate BAY x 3702 (0.1 mg/kg, i.p.) from vehicle in a standard two-lever fixed ratio 10 food-reinforced procedure. All rats learned the discrimination, the median number of sessions to reach criterion being 38 (range: 22-58 sessions). Generalization tests with BAY x 3702 showed dose-dependent and complete generalization after different routes of administration; the ED50 values being: 0.030, 0.007 and 0.36 mg/kg, after i.p., i.v. and p.o. administration, respectively. Assessment of the duration of action after administration of 0.1 mg/kg BAY x 3702, i.p., resulted in a T1/2 of 65 min. Dose-dependent and complete generalization was also obtained with the 5-HT1A receptor agonists 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)-tetralin, ED50 in mg/kg, i.p.: 0.086), flesinoxan (0.30), SR 57746A ((4-(3-trifluoromethylphenyl)-N-(2-(naphth-2-yl)ethyl)-1,2,3,6-tet rahydropyridine HCl, 1.0), the (+)-enantiomer of BAY x 3702 (1.3) and ipsapirone (1.8); the ED50 values being closely correlated with their respective affinities for the 5-HT1A receptor. Pretreatment with the selective 5-HT1A receptor antagonist WAY-100635 ((N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N(2-pyridinyl) cyclohexane carboxamide trihydrochloride) dose-dependently and completely blocked the discriminative effects of 0.1 mg/kg BAY x 3702 (ID50: 0.013 mg/kg, i.p.). WAY-100635, prazosin, idazoxan, raclopride, paroxetine, (-)-BAY k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-p yridine-5-carboxylate), ethanol, and the putative neuroprotectants MK-801 ((+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e), CNS 1102 (N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methyl-guanidine), CGS 19755 (cis-4-(phosphonomethyl) piperidine-2-carboxylic acid) and nimodipine did not induce more than 20% generalization. It is concluded that the BAY x 3702 cue is mediated by its agonistic activity at 5-HT1A receptors.
氨基甲基色满衍生物BAY x 3702（R-(-)-2-｛4-[(色满-2-基甲基)-氨基]-丁基｝-1,1-二氧代-苯并[d]异噻唑啉盐酸盐）最近被鉴定为一种相对选择性的、高亲和力的5-HT1A受体激动剂，在动物模型中具有神经保护、抗焦虑和抗抑郁样作用。本研究的目的是在体内试验中进一步确认其受体结合特征。在标准的双杠杆固定比率10食物强化程序中，训练大鼠区分BAY x 3702（0.1 mg/kg，腹腔注射）和溶剂。所有大鼠都学会了这种区分，达到标准的会话中位数为38次（范围：22-58次会话）。用BAY x 3702进行的泛化试验显示，不同给药途径后呈剂量依赖性且完全泛化；腹腔注射、静脉注射和口服给药后的ED50值分别为：0.030、0.007和0.36 mg/kg。腹腔注射0.1 mg/kg BAY x 3702后评估其作用持续时间，得出T1/2为65分钟。5-HT1A受体激动剂8-OH-DPAT（8-羟基-2-(二正丙基氨基)-四氢萘，腹腔注射的ED50，mg/kg：0.086）、氟司哌隆（0.3）、SR 57746A（(4-(3-三氟甲基苯基)-N-(2-(萘-2-基)乙基)-1,2,3,6-四氢吡啶盐酸盐，1.0）、BAY x 3702的(+)-对映体（1.3）和伊沙匹隆（1.8）也得到了剂量依赖性和完全泛化；ED50值与其对5-HT1A受体的各自亲和力密切相关。用选择性5-HT1A受体拮抗剂WAY-100635（(N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-(2-吡啶基)环己烷甲酰胺三盐酸盐）预处理剂量依赖性地并完全阻断了0.1 mg/kg BAY x 3702的辨别作用（ID5：0.013 mg/kg，腹腔注射）。WAY-100635、哌唑嗪、咪唑克生、雷氯必利、帕罗西汀、(-)-BAY k 8644（甲基-1,4-二氢-2,6-二甲基-3-硝基-4-(2-三氟甲基苯基)-吡啶-5-羧酸盐）、乙醇以及假定的神经保护剂MK-801（(+)-5-甲基-10,11-二羟基-5H-二苯并(a,d)环庚烯-5,10-亚胺））、CNS 1102（N-(1-萘基)-N'-(3-乙基苯基)-N'-甲基胍）、CGS 19755（顺式-4-(膦酰甲基)哌啶-2-羧酸）和尼莫地平诱导的泛化不超过20%。得出的结论是，BAY x 3702线索是由其对5-HT1A受体的激动活性介导的。
