Investigations on the 1-(2-Biphenyl)piperazine Motif: Identification of New Potent and Selective Ligands for the Serotonin₇ (5-HT₇) Receptor with Agonist or Antagonist Action in Vitro or ex Vivo

Abstract

Here we report the design, synthesis, and 5-HT(7) receptor affinity of a set of 1-(3-biphenyl)- and 1-(2-biphenyl)piperazines. The effect on 5-HT(7) affinity of various substituents on the second (distal) phenyl ring was analyzed. Several compounds showed 5-HT(7) affinities in the nanomolar range and >100-fold selectivity over 5-HT(1A) and adrenergic α(1) receptors. 1-[2-(4-Methoxyphenyl)phenyl]piperazine (9a) showed 5-HT(7) agonist properties in a guinea pig ileum assay but blocked 5-HT-mediated cAMP accumulation in 5-HT(7)-expressing HeLa cells.

Novel agonists for serotonin 5-HT7 receptors reverse metabotropic glutamate receptor-mediated long-term depression in the hippocampus of wild-type and Fmr1 KO mice, a model of Fragile X Syndrome

“…The synthesis of the following 5-HT 7 receptor ligands was accomplished as previously reported: N -(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide, LP-211 (Leopoldo et al, 2008), ( R )-1-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-pyrazinyloxy)-2-propanol, BA-10 (Hansen et al, 2014), N-(2-fluoropyridin-5-ylmethyl)-4-[2-(4-methoxy)phenyl]-1-pip erazinehexanamide, PF-62 (Lacivita et al, 2014), 1-(2-biphenyl)piperazine, RA-7 (Bantle, 1996), 1-[2-(4-methoxyphenyl)phenyl]piperazine, PM-20 (Lacivita et al, 2012). N -(4-cyanophenylmethyl)-3-[4-[2-(4-methoxyphenyl)phenyl]pipe-razin-1-yl]ethoxy]propanamide, MM-1, and N -(4-trifuoromethylphenylmethyl)-3-[4-[2-(4-methoxyphenyl)phenyl]pipe-razin-1-yl]ethoxy]propanamide, MM-2, were synthesized as depicted in Figure 1 (Scheme 1).…”

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

“…The study allowed us to identify some potent 5-HT 1A (5, 14, 17-21), 5-HT 7 (17,18,20) and mixed 5-HT 1A /5-HT 7 (12,15,21) receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The study reveals that 5-HT 1A and 5-HT 7 receptor affinity benefits from the introduction of a fluorine moiety while introduction of imidazole ring into 7, 8 position of theophylline had no significant effect on inhibitory potencies for selected PDE.…”

“…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.…”