Ahlgren Charlotte, Eriksson Anders, Tellefors Pernilla, Ross Svante B, Stenfors Carina, Malmberg Asa
Department of Molecular Pharmacology, Local Discovery Research Area CNS & Pain Control, Astrazeneca R&D Södertälje S-151 85, Sweden.
Eur J Pharmacol. 2004 Sep 19;499(1-2):67-75. doi: 10.1016/j.ejphar.2004.07.067.
The in vitro pharmacological properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel 5-hydroxytryptamine (5-HT)(1B) receptor antagonist, were studied. AR-A000002 bound with high affinity to guinea pig cortex and recombinant guinea pig 5-HT(1B) receptors (Ki=0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT(1D) receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [35S]GTPgammaS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a pA2 value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the outflow of [3H]5-HT upon electrical stimulation. The compound blocked sumatriptan-evoked contraction of rabbit saphenous veins without inducing any contraction itself. Thus, in these two systems AR-A000002 behaved as a 5-HT(1B) receptor antagonist. It is concluded that AR-A000002 is a selective high affinity 5HT(1B) receptor ligand that shows partial agonist activity in recombinant systems. In native tissues AR-A000002 behaves as a 5-HT(1B) receptor antagonist.
对新型5-羟色胺（5-HT）（1B）受体拮抗剂AR-A000002（（R）-N-[5-甲基-8-（4-甲基哌嗪-1-基）-1,2,3,4-四氢-2-萘基]-4-吗啉代苯甲酰胺）的体外药理学特性进行了研究。AR-A000002与豚鼠皮层和重组豚鼠5-HT（1B）受体具有高亲和力（Ki分别为0.24和0.47 nM），而与5-HT（1D）受体的亲和力低10倍。该化合物对所测试的其他63个结合位点显示出弱亲和力或无亲和力。在[35S]GTPγS试验中，AR-A000002显示出50%的效能，抑制5-HT刺激的程度为66%，pA2值为8.9。在豚鼠皮层切片中，AR-A000002在电刺激时增强了[3H]5-HT的流出。该化合物阻断了舒马曲坦引起的兔隐静脉收缩，而其本身不引起任何收缩。因此，在这两个系统中，AR-A000002表现为5-HT（1B）受体拮抗剂。得出的结论是，AR-A000002是一种选择性高亲和力的5HT（1B）受体配体，在重组系统中表现出部分激动剂活性。在天然组织中，AR-A000002表现为5-HT（1B）受体拮抗剂。
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