CENTRALLY ACTING HYPOTENSIVE AGENTS WITH AFFINITY FOR 5-HT1A BINDING-SITES INHIBIT FORSKOLIN-STIMULATED ADENYLATE-CYCLASE ACTIVITY IN CALF HIPPOCAMPUS
CENTRALLY ACTING HYPOTENSIVE AGENTS WITH AFFINITY FOR 5-HT1A BINDING-SITES INHIBIT FORSKOLIN-STIMULATED ADENYLATE-CYCLASE ACTIVITY IN CALF HIPPOCAMPUS
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DOI：
10.1111/j.1476-5381.1988.tb11728.x
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发表时间：
1988-11-01
影响因子：
7.3
通讯作者：
HOYER, D
中科院分区：
文献类型：
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作者：
SCHOEFFTER, P;HOYER, D
一些中枢作用的消肿剂和其他配体与5-羟色胺1A（5-HT 1A）识别位点的高亲和力已测试毛喉素刺激的腺苷酸环化酶活性在小牛海马，5-HT 1A受体的功能模型。参比5-HT 1受体激动剂引起对毛喉素刺激的腺苷酸环化酶活性的浓度依赖性抑制（平均EC 50值，nM）：5-羟色胺（22），5-羧酰胺色胺（5-CT，3.2），8-羟基-2-（二正丙胺基）四氢萘（8-OH-DPAT，8.6），N，N-二丙基-5-羧酰胺色胺（DP-5-CT，2.3）、1-[2-（4-氨基苯基）乙基]-4-（3-三氟甲基苯基）-哌嗪（PAPP或LY 165163，20）、5-甲氧基-3-（1，2，3，6-四氢-4-吡啶基）-1H吲哚（RU 24969，20）、丁螺环酮（65）和伊沙匹隆（56）。除了后两种激动剂（14%）外，所有药物的Emax抑制率均为18-20%。以下对5-HT 1A位点具有高亲和力的抑制剂是该系统中的有效激动剂（平均EC 50值，nM）：氟辛克生（24）、吲哚烯酸酯（99）、异丙基-1-{1-[2-（1，4-苯并二恶烷-2-基）-2-羟乙基]-4-哌啶基}-2-苯并咪唑啉酮（R 28935，2.5）、乌拉地尔（390）和5-甲基乌拉地尔（3.5）。前两种药物为完全激动剂，而后三种药物为部分激动剂，疗效为60-80%。Metergoline和methysergide表现为完全激动剂，而氰基吲哚洛尔表现为部分激动剂，疗效较低。Spiroxatrine和2-（2，6-二甲氧基苯氧基乙基）氨甲基-1，4-苯并二氧六环（WB 4101），结合5-HT 1A网站与纳摩尔亲和力，是激动剂，并有效地抑制毛喉素刺激的腺苷酸环化酶在小牛海马，显示平均EC 50值分别为23和15 μ mol/L。Spiroxatrine和WB 4101的疗效分别为90%和50%。螺哌隆和甲硫替平（各1 μ M）引起浓度-效应曲线向8-OH-DPAT的10%移动，而不丧失最大效应，部分激动剂氰基吲哚洛尔（0.1 μ M）和（sbd）-和吲哚洛尔的（+）-对映体（分别为1 μ M和0.1 mM）。19种腺苷酸环化酶激动剂的pEC_（50）值（6.4 ~ 8.7）与5-HT_（1A）识别位点的pKD值之间有很好的相关性（r = 0.90，P = 0.0001）。腺苷酸环化酶拮抗剂的表观pKB值与5-HT 1A结合位点的pKD值也显著相关。本研究进一步表明，海马5-HT 1A识别位点与5-HT受体介导的腺苷酸环化酶抑制作用是相同的。数据显示，在该模型中，许多对5-HT 1A位点具有高亲和力的中枢作用的促渗剂是有效的激动剂，表明中枢5-HT 1A受体参与血压的控制。
A number of centrally acting hypotensive agents and other ligands with high affinity for 5-hydroxytryptamine1A (5-HT1A) recognition sites have been tested on forskolin-stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5-HT1A-receptors. Concentration-dependent inhibition of forskolin-stimulated adenylate cyclase activity was elicited by the reference 5-HT1-receptor agonists (mean EC50 value, nM): 5-HT (22), 5-carboxamidotryptamine (5-CT, 3.2), 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 8.6), N,N-dipropyl-5-carboxamidotryptamine (DP-5-CT, 2.3), 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (PAPP or LY 165163, 20), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). Emax amounted to 18-20% inhibition for all but the latter two agonists (14%). The following hypotensive agents with high affinity for 5-HT1A sites were potent agonists in this system (mean EC50 value, nM): flesinoxan (24), indorenate (99), erythro-1-{1-[2-(1,4-benzodioxan-2-yl)-2-hydroxyethyl]-4-piperidyl}-2-benzimidazolinone (R 28935, 2.5), urapidil (390) and 5-methylurapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60-80% efficacy. Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 n,, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively. Spiperone and methiothepin(each 1 .mu.M) caused rightward shifts of the concentration-effect curve to 8-OH-DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 .mu.M) and the (.sbd.)- and (+)-enantiomers of pindolol (1 .mu.M and 0.1 mM, respectively). There was an excellent correlation (r = 0.90, P = 0.0001) between the pEC50 values (ranging from 6.4 to 8.7) of the 19 agoniststested at adenylate cyclase and their pKD for 5-HT1A recognition sites. Apparent pKB values of antagonists at adenylate cyclase and their pKD values for 5-HT1A binding sites were also significantly correlated. This study further indicates that the 5-HT1A recognition site and the 5-HT receptor mediating inhibition of adenylate cyclase in hippocampus are the same. The data show that a number of centrally acting hypotensive agents with high affinity for the 5-HT1A site are potent agonists in this model, suggesting an involvement of central 5-HT1A-receptors in the control of blood pressure.