Dukić S, Kostić-Rajacić S, Dragović D, Soskić V, Joksimović J
Institute for Biological Research, Belgrade, Yugoslavia.
J Pharm Pharmacol. 1997 Oct;49(10):1036-41. doi: 10.1111/j.2042-7158.1997.tb06037.x.
Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT1A ligands. For this purpose 1-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2-thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure-affinity requirements of 1-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT1A receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT1A selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H]spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d-3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]-1-(2-methoxyphenyl)piperazine, 3a (Ki = 1.7 nM). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c-3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT1A receptors (Ki = 2.6 nM). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.
为了合成新型的D2/5HT1A混合配体，已合成了22种不同的化合物。为此，根据1-芳基哌嗪已知的结构-亲和力要求，选择通过N-4氮连接到2-(5-苯并咪唑)乙基、2-(5-苯并三唑)乙基、2-[5-(苯并咪唑-2-硫酮)]乙基和2-[6-(1,4-二氢喹喔啉-2,3-二酮)]乙基类型的多巴胺能药效基团上的1-取代苯基哌嗪。对所有新化合物进行了多巴胺（D1和D2）和5-HT1A受体的体外结合亲和力评估。分别从新鲜牛尾状核和海马体制备的突触体膜用作多巴胺和5-羟色胺受体的来源。[3H]SCH 23390（D1选择性）、[3H]螺哌隆（D2选择性）和8-OH-[3H]DPAT（5-HT1A选择性）用作放射性配体。没有一种化合物对D1多巴胺受体表现出结合亲和力。化合物3b和4b是无活性的8-OH-[3H]DPAT竞争剂，而1b、2b和4b在[3H]螺哌隆结合试验中无活性。所测试的其他化合物在[3H]螺哌隆结合试验中表现出中等（1c、1e、1f、2c、2f、3b、3c和4c）至高（1a、1d、2a、1d、3a、3d - 3f、4a和4d）亲和力，最有效的代表物是4-[2-(5-苯并咪唑-2-硫酮)乙基]-1-(2-甲氧基苯基)哌嗪，3a（Ki = 1.7 nM）。在8-OH-[3H]DPAT置换试验中，化合物1b、1d、1f、2b、2f和3f表现为中等竞争剂，1a、1c、1e、2a、2c、2d、3a、3c - 3e、4a、4c、4d和4f表现为较强竞争剂；4-[2-(5-苯并三唑)乙基]-1-(2-甲氧基苯基)哌嗪，2a在5-HT1A受体上具有最高的结合亲和力（Ki = 2.6 nM）。由于许多抗精神病药和抗焦虑药表现为多巴胺能和5-羟色胺能混合配体，这些新配体中的几种对D2和5-HT1A受体的高亲和力使其成为有前途的候选物，值得作为抗精神病药或抗焦虑药进行进一步的药理学评估。
