褪黑素受体拮抗剂,区分人类Mel1a和Mel1b重组亚型是用来评估兔视网膜的药理ML1中引入突触前heteroreceptor。

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Dubocovich ML, Masana MI, Iacob年代,绍DM

褪黑素受体拮抗剂,区分人类Mel1a和Mel1b重组亚型是用来评估兔视网膜的药理ML1中引入突触前heteroreceptor。

Naunyn Schmiedebergs拱杂志。1997年3月,355 (3):365 - 75。

PubMed ID

9089668 (在PubMed

]

文摘

我们已经识别出亚型选择性受体激动剂,局部受体激动剂和拮抗剂,区分人类重组Mel1a和Mel1b褪黑激素受体表达COS-7细胞。褪黑激素受体受体激动剂显示更高的亲和力2 - [125 i] -iodomelatonin绑定的竞争比Mel1a Mel1b褪黑素受体。16个受体激动剂的离解常数(Ki)决定重组人类Mel1a和Mel1b褪黑素受体亚型呈显著相关(r2 = 0.85,斜率= 0.97,P < 0.0001, n = 16)。然而,6受体激动剂显示10到60倍更高的亲和力Mel1b褪黑素受体的亲和力选择性比率(Mel1a / Mel1b) [8-methoxy-2-acetamidotetraline (11);S20098 (14);8-methoxy-2-propionamidotetraline (20);6、7 di-chloro-2-methylmelatonin (21);6-chloromelatonin (57);6-methoxymelatonin (59)]。离解常数为竞争11部分受体激动剂和拮抗剂2 - [125 i] -iodomelatonin绑定之间15.5 (luzindole, pKi: 7.7)到362 (4-phenyl-2-chloroacetamidotetraline pKi: 9.1)褶皱为Mel1b高于Mel1a褪黑素受体。 The lack of correlation between the pKi values (r2 = 0.23, P > 0.1, n = 11) strongly suggest that the two human melatonin receptor subtypes can be distinguished pharmacologically. The partial agonist: 5-methoxyluzindole (pKi: 9.6) and the competitive melatonin receptor antagonists: GR128107 (pKi: 9.6), 4-phenyl-2-chloroacetamidotetraline (pKi: 9.1), 4-phenyl-2-acetamidotetraline (pKi: 8.9) and 4-phenyl-2-propionamidotetraline (pKi: 8.8) are selective Mel1b melatonin receptor analogues as their affinity selectivity ratios (Mel1a/Mel1b) are bigger than 100. We conclude that the 40% overall amino acid difference in the sequence of the human recombinant Mel1a and Mel1b melatonin receptors is reflected in distinct pharmacological profiles for the subtypes. We compared the pharmacological profile of the presynaptic ML1 melatonin heteroreceptor of rabbit retina mediating inhibition of the calcium-dependent release of dopamine to that of the recombinant Mel1a and Mel1b melatonin receptors. Melatonin inhibited [3H]dopamine release by 50% (1C50) at 20 pM with a maximal inhibitory effect (80%) at 1 nM. The partial agonists, i.e., N-acetyltryptamine (1C50 5.6, maximal inhibition 55%) and 5-methoxyluzindole (1C50: 1.3, maximal inhibition 40%) showed various degrees of efficacy while none of the competitive melatonin receptor antagonists did inhibit [3H]dopamine release on their own. The potency (1C50) of full melatonin receptor agonists significantly correlated with their affinity to compete for 2-[125I]-iodomelatonin binding to either the Mel1a (r2 = 0.76, slope = 0.77, P < 0.0001, n = 17) or Mel1b (r2 = 0.63, slope = 0.75, P < 0.001, n = 17) human melatonin receptors. By contrast, the apparent dissociation constants (KB) for partial agonists and antagonists to antagonize the inhibition of [3H]dopamine release mediated by activation of the ML1 heteroreceptor by melatonin, significantly correlated with the affinity constants (Ki) for 2-[125I]-iodomelatonin binding determined of the Mel1b (r2 = 0.77, slope = 0.55, P < 0.001; n = 11) but not the Mel1a (r2 = 0.27, P < 0.1, n = 11) subtype. Together these results demonstrate that the pharmacological profile of the human recombinant Mel1b melatonin receptor is similar to that of the functional presynaptic melatonin heteroreceptor of rabbit retina, which we referred as an ML1B subtype. We conclude that the selective Mel1b melatonin partial agonists and antagonists described here can be used to identify melatonin receptor subtypes in native tissues and to search for subtype selective analogues with therapeutic potential.

DrugBank数据引用了这篇文章

绑定属性

药物	目标	财产	测量	pH值	温度(°C)
Agomelatine	褪黑激素受体1 b型	Ki (nM)	0.06	N /一个	N /一个	细节
褪黑激素	褪黑激素受体1 b型	Ki (nM)	0.18	N /一个	N /一个	细节