- Characterization of the 5-HT7 Receptor. Determination of the Pharmacophore for 5-HT7 Receptor Agonism and CoMFA-Based Modeling of the Agonist Binding Site
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On the basis of a set of 20 diverse 5-HT7 receptor agonists, the pharmacophore for 5-HT7 receptor agonism was determined. Additionally two CoMFA models were developed, based on different alignments of the agonists. Both models show good correlations between experimental and predictive pKi values and show a high degree of similarity. The CoMFA fields were subsequently used to map the agonist binding site of the model of the 5-HT7 receptor. Important roles in ligand binding are attributed to Asp162 of TM3 (interaction with a protonated nitrogen), and Thr244 of TM5 (interaction with a substituent at an aromatic moiety). Amino acid residues of the aromatic cluster of TM6 are hypothesized to play an important role in ligand binding as π-π stacking moieties. Agonists missing a hydrogen-bond-accepting moiety, but possessing an aromatic substituent instead, seem to bind the receptor with high affinity as well by occupying a lipophilic pocket hosted by residues of TM5 and TM6.
- Vermeulen, Erik S.,Schmidt, Anne W.,Sprouse, Jeffrey S.,Wikstr?m, H?kan V.,Grol, Cor J.
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- Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7- methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3, 5-dione: A novel 5-HT1A receptor agonist positron emission tomography ligand
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Antagonist 5-HT1A PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-11C]2-{4-[4-(7- methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3, 5-dione (10), a potential high affinity (Ki = 1,36 nM) 5-HT 1A agonist PET tracer is described. Piperazine 10 is a 5-HT 1A agonist with an EC50 comparable to serotonin, based on cAMP formation and GTPγS binding assays. Radiosynthesis of [ 11C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1- yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [ 11C]CH3OTf in 25 ± 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [11C]10 were >99% with a specific activity 1500 ± 300 Ci/mmol (n = 15). PET studies in anesthetized baboon demonstrate [11C]10 specific binding in brain regions rich in 5-HT1A receptors. Binding of [ 11C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (VT) of [11C]10 in baboon correlate with [11C]WAY100635 VT in baboons. These data provide evidence that [11C]10 is the first promising agonist PET tracer for the 5-HT1A receptors.
- Kumar, J.S. Dileep,Majo, Vattoly J.,Hsiung, Shu-Chi,Millak, Matthew S.,Liu, Kuo-Peing,Tamir, Hadassah,Prabhakaran, Jaya,Simpson, Norman R.,Van Heertum, Ronald L.,Mann, J. John,Parsey, Ramin V.
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