The Extracellular Entrance Provides Selectivity to Serotonin 5-HT₇ Receptor Antagonists with Antidepressant-like Behavior in Vivo

Abstract

The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

“…[11] In this work, we will name this cavity as receptorv estibule or exosite. Bitopicl igandst hat targett he orthosteric site and the receptor vestibule improve selectivity, [11,12] off-rates and signalingb ias, [4,13,14] maintaining bioavailability and brain penetration properties in mice. [15] Othert ype of comparable ligands are designed to simultaneously bind two orthosteric sites of a( homo/hetero) GPCR dimer.…”

Discovery of Homobivalent Bitopic Ligands Of The Cannabinoid Cb2 Receptor

“…Binding affinities of alkoxychromenopyrazoles (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) for hCB 1 R and hCB 2 R. Table S1. Binding affinities of alkoxychromenopyrazoles (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) for hCB 1 R and hCB 2 R. Figure S1. (A) Ab initio torsional energy profile (HF/6-31G*//HF/6-31G*) of the C1-O2-C3-C4 dihedral angle (in blue) for chromenopyrazole derivatives A (N1-Ethyl, black circle) and B (N2-Ethyl, white circle) in which the hexyl chains were substituted by methyl.…”

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.…”