Testa R, Guarneri L, Poggesi E, Angelico P, Velasco C, Ibba M, Cilia A, Motta G, Riva C, Leonardi A
Pharmaceutical Research and Development Division, Recordati S.p.A., Milan, Italy.
J Pharmacol Exp Ther. 1999 Sep;290(3):1258-69.
Several novel N-arylpiperazine derivatives were synthesized and tested for their 1) affinity and functional activity on 5-hydroxytryptamine(1A) (5-HT(1A)) receptors in vitro; 2) activity in models predictive of antagonism at somatodendritic and postsynaptic 5-HT(1A) receptors; and 3) effects on the micturition reflex in anesthetized and conscious rats. These studies also included 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN 190), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4, 5]decane-7,9-dione dihydrochloride (BMY 7378), and N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohex anecarboxamide (WAY 100635). Almost all compounds were found to be potent and selective for the human recombinant 5-HT(1A) receptor, with K(i) values in the nanomolar range. [(35)S]GTPgammaS binding in HeLa cells expressing the recombinant human 5-HT(1A) receptor allowed classification of the compounds into neutral antagonists and partial agonists. Almost all neutral antagonists were active in blocking 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT)-induced forepaw treading in rats (postsynaptic model) and hypothermia in mice (somatodendritic model) with the same potency, whereas compounds showing partial agonistic activity were active in the postsynaptic model but were inactive, or poorly active, in the somatodendritic model. Neutral antagonists potently inhibited volume-induced bladder-voiding contractions in anesthetized rats. Contractions were completely blocked, and the disappearance of bladder contractions lasted 7 to 13 min after the highest doses tested. Furthermore, neutral antagonists increased bladder volume capacity in conscious rats during continuous transvesical cystometry, whereas micturition pressure was only slightly, and not dose-dependently, reduced. Partial agonists were inactive or poorly active, inducing a disappearance time of bladder contractions that did not exceed 6 min in anesthetized rats, and failing to increase bladder volume capacity in conscious rats. These findings indicate that only neutral 5-HT(1A) receptor antagonists are endowed with inhibitory effects on the bladder.
合成了几种新型的N-芳基哌嗪衍生物，并对其进行了如下测试：1）在体外对5-羟色胺（1A）（5-HT（1A））受体的亲和力和功能活性；2）在预测对树突体和突触后5-HT（1A）受体拮抗作用的模型中的活性；3）对麻醉和清醒大鼠排尿反射的影响。这些研究还包括1-（2-甲氧基苯基）-4-[4-（2-邻苯二甲酰亚胺基）丁基]哌嗪氢溴酸盐（NAN 190）、8-[2-[4-（2-甲氧基苯基）-1-哌嗪基]乙基]-8-氮杂螺[4,5]癸烷-7,9-二酮二盐酸盐（BMY 7378）和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（WAY 100635）。几乎所有化合物对人重组5-HT（1A）受体都具有强效和选择性，其抑制常数（K(i)）值在纳摩尔范围内。在表达重组人5-HT（1A）受体的HeLa细胞中进行的[(35)S]GTPγS结合实验，可将这些化合物分为中性拮抗剂和部分激动剂。几乎所有中性拮抗剂在阻断大鼠8-羟基-2-二丙基氨基四氢萘（8-OH-DPAT）诱导的前爪踏地（突触后模型）和小鼠体温过低（树突体模型）方面具有相同效力，而表现出部分激动活性的化合物在突触后模型中具有活性，但在树突体模型中无活性或活性较弱。中性拮抗剂能有效抑制麻醉大鼠中容量诱导的膀胱排尿收缩。收缩被完全阻断，在测试的最高剂量后，膀胱收缩消失持续7至13分钟。此外，在连续经膀胱膀胱测压过程中，中性拮抗剂增加了清醒大鼠的膀胱容量，而排尿压力仅略有降低且无剂量依赖性。部分激动剂无活性或活性较弱，在麻醉大鼠中诱导膀胱收缩消失的时间不超过6分钟，且在清醒大鼠中未能增加膀胱容量。这些发现表明，只有中性5-HT（1A）受体拮抗剂对膀胱具有抑制作用。
