Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our studies on 4-amino-5-chloro-2-ethoxybenzamides led to the discovery that the N-(1,4-dimethylhexahydro-1H-1,4-diazepin-6-yl)benzamide 9 and the 1-benzyl-4-methylhexahydro-1H-1,4-diazepine analogue 10 are potent serotonin-3 (5-HT3) receptor antagonists. Structure-activity relationship (SAR) studies on the influence of the aromatic nucleus of 9 and 10 upon inhibition of the von Bezold-Jarisch reflex in rats are described. Heteroaromatic rings such as pyrrole, thiophene, furan, pyridine, pyridazine, 1,2-benzisoxazole, indole, quinoline, and isoquinoline rings showed weak 5-HT3 receptor antagonistic activity. Within this series, use of the 1H-indazole ring as an aromatic moiety led to a substantial increase of the activity; the 1H-indazolylcarboxamides 54, 57, 97, and 102 showed potent 5-HT3 receptor antagonistic activity. The optimal compound identified via extensive SAR studies was N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indaz ole-3- carboxamide (54), whose effect was superior to that of the corresponding benzamide 10 and essentially equipotent to those of ondanbsetron (1) and granisetron (4).
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PMID:Development of potent serotonin-3 (5-HT3) receptor antagonists. II. Structrue-activity relationships of N-(1-benzyl-4-methylhexahydro-1H-1,4- diazepin-6-yl)carboxamides. 857 32

Synthesis and pharmacological evaluation of a series of condensed quinoline and pyridine derivatives bearing a N-methylpiperazine moiety attached to the 2-position of the quinoline or pyridine nucleus are described. 5-HT receptor binding studies revealed subnanomolar affinity for the 5-HT3 receptor subtype in some of the compounds under study. The most active compound (5b) displayed a Ki value about 1 order of magnitude higher than that of quipazine along with a higher selectivity. The potential 5-HT3 agonist/antagonist activity of four selected compounds was assessed in vitro on 5-HT3 receptor-dependent [14C]guanidinium uptake in NG 108-15 cells. Compound 5j acted as a 5-HT3 agonist in this assay with an EC50 value close to that reported for quipazine, while 5b was a partial agonist with an EC50 value of about 0.25 nM, and compound 5c possessed antagonist properties with an IC50 value (approximately 8 nM) in the same range as those of previously characterized 5-HT3 receptor antagonists. Qualitative and quantitative structure-affinity relationship studies carried out by making use of theoretical molecular descriptors allowed to elucidate the role of the main pharmacophoric components and to develop a model for the interaction of the 5-HT3 ligands related to quipazine with their receptor.
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PMID:Novel potent and selective central 5-HT3 receptor ligands provided with different intrinsic efficacy. 1. Mapping the central 5-HT3 receptor binding site by arylpiperazine derivatives. 951 1

The lead compound of a new series of 3-pyridyl ethers, the azetidine derivative A-85380 (3-[(S)-2-azetidinylmethoxy]pyridine), is a potent and selective ligand for the human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtype. In vitro, the fluoro derivative of A-85380 (2-fluoro-3-[(S)-2-azetidinylmethoxy]pyridine or F-A-85380) competitively displaced [3H]cytisine or [3H]epibatidine with Ki values of 48 and 46 pM, respectively. F-A-85380 has been labeled with the positron emitter fluorine-18 (t1/2 (half-life) = 110 min) by no-carrier-added nucleophilic aromatic substitution by K[18F]F-K222 complex with (3-[2(S)-N-(tert-butoxycarbonyl)-2-azetidinylmethoxy]pyridin-2-yl) tri methylammonium trifluoromethanesulfonate as a highly efficient labeling precursor, followed by TFA removal of the Boc protective group. The total synthesis time was 50-53 min from the end of cyclotron fluorine-18 production (EOB). Radiochemical yields, with respect to initial [18F]fluoride ion radioactivity, were 68-72% (decay-corrected) and 49-52% (non-decay-corrected), and the specific radioactivities at EOB were 4-7 Ci/micromol (148-259 GBq/micromol). In vivo characterization of [18F]F-A-85380 showed promising properties for PET imaging of central nAChRs. This compound does not bind in vivo to alpha7 nicotinic or 5HT3 receptors. Moreover, its cerebral uptake can be modulated by the synaptic concentration of the endogenous ligand acetylcholine. The preliminary PET experiments in baboons with [18F]F-A-85380 show an accumulation of the radiotracer in the brain within 60 min. In the thalamus, a nAChR-rich area, uptake of radioactivity reached a maximum at 60 min (4% I.D./100 mL of tissue). [18F]F-A-85380 appears to be a suitable radioligand for brain imaging nAChRs with PET.
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PMID:Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine: a new positron emission tomography ligand for nicotinic receptors. 1037 31

We developed an engineered site-directed labeling method (Foucaud et al., 2001) to investigate ligand receptor interactions on the acetylcholine (ACh)- binding site of nicotinic acetylcholine receptors (nAChRs). The method uses cysteine receptor mutants, together with cysteine-reactive ligand analogs, to generate a site-directed covalent reaction within the binding site. We selected epibatidine (EPB) as a prototypical ligand, acting at all types of nAChRs with sufficient affinity to allow this study. Accordingly, we synthesized three cysteine-reactive derivatives, all modified at the C-3 of the pyridine ring of the alkaloid with NCS; -NHCOCH2Cl, and -CH2Cl groups, respectively (Fig. 1). The binding properties have been established on rat brain, alpha7-5HT3 chimera, and Torpedo membranes, respectively, whereas the functional properties were tested on alpha4beta2 and alpha7 receptor expressed in oocytes and Cys-less muscular receptor expressed in HEK cells (Sakr et al., 2005).
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PMID:Engineered site-directed labeling of nicotinic acetylcholine receptors using reactive epibatidine derivatives: appraisal of epibatidine-docking models in neuronal and muscular receptors. 1719 18