Novel 5-HT₇Receptor Inverse Agonists. Synthesis and Molecular Modeling of Arylpiperazine- and 1,2,3,4-Tetrahydroisoquinoline-Based Arylsulfonamides

Abstract

A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT7 receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT7. All ligands produced a decrease of adenylate cyclase activity, indicative of their inverse agonism. Additionally, computational studies with a set of 22 inverse agonists, including these novel inverse agonists and inverse agonists known from literature, resulted in a pharmacophore model and a CoMFA model (R2 = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT7 receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.

Identification of a Potent Inverse Agonist at a Constitutively Active Mutant of Human P2Y12 Receptor

“…Although there are no clinical data indicating that an inverse agonist demonstrates superior clinical efficacy over the pure antagonists, data from numerous in vitro (Dupre et al, 2004;Mahe et al, 2004;Tryoen-Toth et al, 2004;Vermeulen et al, 2004;Vertongen et al, 2004) and some in vivo studies (Bond et al, 1995;Adan and Kas, 2003;Schwartz et al, 2003) have demonstrated the potential therapeutic advantage of inverse agonists. Many clinically important medicines have been demonstrated to behave as inverse agonists when tested against either wild-type or mutated GPCRs (Milligan, 2003); we believe, to some extent, that this evidence highlights the potential advantage of inverse agonists over neutral antagonists.…”

Pharmacophore Models for Metabotropic 5-HT Receptor Ligands

“…(17)). The 4 aligned agonists, together with 3 other less active agents (93,97,98), were then used in CoMFA study. Different combinations of steric and electrostatic fields with a lipophilic potential or logP parameter were analyzed, and it turned out that models with overlapping (a 5-hydroxyl oxygen, the centroid of an adjacent aromatic ring and a protonated nitrogen atom); as to the second, its ligand alignment was guided by the receptor binding site.…”

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

“…Mice were individually placed in a glass cylinder (25 cm high; 10 cm in diameter) containing 10 cm of water maintained at [23][24][25] C and were left there for 6 min. A mouse was regarded as immobile when it remained floating on the water, making only small movements to keep its head above it.…”

“…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.…”