Synthesis of New Serotonin 5-HT₇ Receptor Ligands. Determinants of 5-HT₇/5-HT_1A Receptor Selectivity

Abstract

We report the synthesis of a new set of compounds of general structure I (1-20) with structural modifications in the pharmacophoric elements of the previously reported lead UCM-5600. The new derivatives have been evaluated for binding affinity at 5-HT(7) and 5-HT(1A) receptors. The influence of the different structural features in terms of 5-HT(7)/5-HT(1A) receptor affinity and selectivity was analyzed by computational simulations of the complexes between compounds I and beta(2)-based 3-D models of these receptors. Compound 18 (HYD(1) = 1,3-dihydro-2H-indol-2-one; spacer = -(CH(2))(4)-; HYD(2) + HYD(3) = 3,4-dihydroisoquinolin-2(1H)-yl) exhibits high 5-HT(7)R affinity (K(i) = 7 nM) and selectivity over the 5-HT(1A)R (31-fold), and has been characterized as a partial agonist of the human 5-HT(7)R.

Comparison of 4 Radiolabeled Antagonists for Serotonin 5-HT7 Receptor Neuroimaging: Toward the First PET Radiotracer

“…This choice was justified by reports of difficulty for some 5-HT 7 ligands in discriminating between 5-HT 1A (21,41,42) and 5-HT 6 receptors (43). We also showed that molecules of the FPMP series presented 5-HT 1A agonistic affinity (EC 50 .…”

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

“…On the basis of the binding affinity results, a series of compounds possessing affinity below 3 nM for 5-HT 1A R (5,8,9,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) and below 50 nM for 5-HT 7 receptors (9,12,15,17,18,20,21) was selected for functional profile characterization. Intrinsic activity studies were performed using in vitro measures of receptor activation.…”

“…Intrinsic activity studies were performed using in vitro measures of receptor activation. No activation of any of the receptors was observed, and the compounds showed antagonist properties, especially the 5-HT 1A (5,9,12,14,15,(17)(18)(19)(20)(21) (Figures 4 and 5). In case of 5-HT 7 R, there are significant differences between the binding and functional tests results for selected compounds.…”

“…A very important class of 5-HT receptors ligands are derivatives of 1,4-disubstituted arylpiperazine ( Figure 1). Such arylpiperazine derivative with longchain substituents incorporated on the basic nitrogen of the phenylpiperazine ring -long-chain arylpiperazines (LCAPs) -are commonly studied classes of bioactive compounds [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . Despite the enormous progress in central nervous system (CNS) drug discovery, particularly in the areas of mood disorders and schizophrenia, new drugs are still being sought.…”

Synthesis of aminopyrrolo[1,2-a]thieno[3,2-e]pyrazine derivatives as serotoninergic 5-HT7 ligands

“…Many ligands have been reported to bind with high affinity to 5-HT 7 receptors and their number is continuously increasing. [17][18][19] In the course of a program aimed at the discovery of new serotonine 5-HT 7 ligands, we submitted to binding assays a range of N-substituted (5-methoxy-3,4-dihydro-2H-1-benzopyran-3-yl)amine derivatives previously studied as 5-HT 1A receptor ligands. [20][21][22] We found that two of them (5-MeO-DPAC and S 20244) displayed significant affinity for 5-HT 7 R. Subsequently, we planned This lack of selectivity has led us to translate the knowledge acquired in the benzopyran series, to aminopyrrolothienopyrazine series, which has been described recently as being the possible support of new 5-HT ligands.…”