Chojnacka-Wójcik E, Kłodzińska A, Tatarczyńska E, Paluchowska M H
Department of New Drug Research, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Pol J Pharmacol. 1999 Sep-Oct;51(5):405-13.
Two new analogs of full 5-HT1A receptor antagonist 4-[3-(1-benzotriazolyl)propyl]-1-(2-methoxyphenyl)piperazine (MP 3022; 1) containing di- (5) or tetramethylene- (6) spacer were synthesized. In the radioligand binding studies, compounds 5 and 6 showed high 5-HT1A (Ki = 14.7 nM and 11.8 nM, respectively) and low 5-HT2 receptor affinity (Ki = 2,696 nM and 389.2 nM, respectively). In behavioral studies both compounds behaved like postsynaptic 5-HT1A receptor antagonists as they reduced lower lip retraction and behavioral syndrome induced by 8-OH-DPAT (5-HT1A receptor agonist) in rats, but 6 was more effective in these tests. Derivative 5 did not affect body temperature in mice, whereas 6 decreased it. Furthermore, 5 did not change hypothermia induced by 8-OH-DPAT, and 6-induced lowering of body temperature in mice was not antagonized by (S)-WAY 100135 (5-HT1A antagonist), so in that model 5 and 6 did not behave as antagonist or agonist, respectively, at presynaptic 5-HT1A receptors. Compound 6 was studied in behavioral tests used to predict a potential anxiolytic (conflict drinking test in rats) and antidepressant (forced swimming test in rats) activity. Diazepam and imipramine were used as reference drugs. Compound 6 significantly increased the number of shocks accepted in water-deprived rats in conflict drinking test and shortened the immobility time in forced swimming test in rats. The above findings indicate that new 5-HT1A postsynaptic antagonist 6 behaves like anxiolytic and antidepressant, but mechanisms of these properties of 6 remain unknown.
合成了全5-羟色胺1A（5-HT1A）受体拮抗剂4-[3-(1-苯并三唑基)丙基]-1-(2-甲氧基苯基)哌嗪（MP 3022；1）的两种新类似物，其含有二亚甲基（5）或四亚甲基（6）间隔基。在放射性配体结合研究中，化合物5和6显示出对5-HT1A具有高亲和力（Ki分别为14.7 nM和11.8 nM），而对5-HT2受体亲和力较低（Ki分别为2,696 nM和389.2 nM）。在行为学研究中，这两种化合物均表现出突触后5-HT1A受体拮抗剂的特性，因为它们能减少大鼠下唇回缩以及由8-OH-DPAT（5-HT1A受体激动剂）诱导的行为综合征，但在这些试验中6更有效。衍生物5对小鼠体温无影响，而6可降低小鼠体温。此外，5不改变由8-OH-DPAT诱导的体温过低，且（S）-WAY 100135（5-HT1A拮抗剂）不能拮抗6诱导的小鼠体温降低，因此在该模型中，5和6在突触前5-HT1A受体处分别未表现出拮抗剂或激动剂的行为。在用于预测潜在抗焦虑（大鼠冲突饮水试验）和抗抑郁（大鼠强迫游泳试验）活性的行为学试验中对化合物6进行了研究。地西泮和丙咪嗪用作参考药物。在冲突饮水试验中，化合物6显著增加了缺水大鼠接受电击的次数，并缩短了大鼠强迫游泳试验中的不动时间。上述研究结果表明，新型突触后5-HT1A拮抗剂6具有抗焦虑和抗抑郁作用，但其这些特性的机制尚不清楚。
