Perez M, Jorand-Lebrun C, Pauwels P J, Pallard I, Halazy S
Medicinal Chemistry Division, Centre de Recherche Pierre FABRE, Castres, France.
Bioorg Med Chem Lett. 1998 Jun 2;8(11):1407-12. doi: 10.1016/s0960-894x(98)00222-4.
New dimers of known 5HT1 ligands (5HT, 1-NP or 8-OH-DPAT) have been prepared and evaluated at human cloned 5HT1B, 5HT1D and 5HT1A receptors. Binding experiments show that all these dimers have better affinities at 5HT1B/1D receptors than their corresponding monomeric ligands. Studies of inhibition of the forskolin-stimulated c-AMP formation mediated by the human 5HT1B receptor show that hetero-bivalent ligands [combining an agonist (5HT) with an antagonist (1-NP)] behave as partial agonists while the intrinsic activity of bivalent antagonists (combining two 1-NP residues) was found to be spacer dependent. Surprisingly enough, the dimer of 8-OH-DPAT 6 binds to 5HT1A, 5HT1B and 5HT1D receptors with similar high affinity.
已制备出已知5-羟色胺1（5HT1）配体（5HT、1-萘基哌嗪或8-羟基二丙胺基四氢萘）的新型二聚体，并在人克隆的5HT1B、5HT1D和5HT1A受体上进行了评估。结合实验表明，所有这些二聚体在5HT1B/1D受体上的亲和力均优于其相应的单体配体。对由人5HT1B受体介导的福斯高林刺激的环磷酸腺苷（c-AMP）形成的抑制作用研究表明，异二价配体[将激动剂（5HT）与拮抗剂（1-萘基哌嗪）结合]表现为部分激动剂，而二价拮抗剂（结合两个1-萘基哌嗪残基）的内在活性则发现与间隔基团有关。令人惊讶的是，8-羟基二丙胺基四氢萘6的二聚体以相似的高亲和力与5HT1A、5HT1B和5HT1D受体结合。
