Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the presence of a 30 nM prazosin mask, [3H]-2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane ([3H]WB4101) can selectively label 5-HT1 serotonin receptors. Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [3H] WB4101 binding in cerebral cortex. Furthermore, we have found a significant correlation (r = 0.96) between the affinities of a number of serotonergic and nonserotonergic compounds at [3H]WB4101-binding sites in the presence of 30 nM prazosin and [3H] lysergic acid diethylamide ([3H]LSD)-labeled 5-HT1 serotonin receptors in homogenates of rat cerebral cortex. Despite similar pharmacological profiles, distribution studies indicate that, in the presence of 5 mM MgSO4, the Bmax of [3H]WB4101 is significantly lower than the Bmax of [3H]LSD in various brain regions. WB4101 competition for [3H] LSD-labeled 5-HT1 receptors fits best to a computer-derived model assuming two binding sites, with the KH for WB4101 being similar to the KD of [3H]WB4101 binding derived from saturation experiments. This suggests that [3H]WB4101 labels only one of the subtypes of the 5-HT1 serotonin receptors labeled by [3H]LSD. Interestingly, the selective 5-HT1A serotonin receptor antagonist, spiperone, and the selective 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetraline, exhibit high affinity and monophasic competition for [3H]WB4101 but compete for multiple [3H]LSD 5-HT1 binding sites. These data indicate that [3H]WB4101 selectively labels the 5-HT1A serotonin receptor, whereas [3H] LSD appears to label both the 5-HT1A and the 5-HT1B serotonin receptor subtypes. The divalent cations, Mn2+, Mg2+, and Ca2+ were found to markedly increase the affinity and Bmax of [3H]WB4101 binding in cerebral cortex. Conversely, the guanine nucleotides guanylylimidodiphosphate and GTP, but not the adenosine nucleotide ATP, markedly reduce the Bmax of [3H]WB4101 binding. These characteristics are typical of agonists interacting with receptors which modulate cellular function via a guanine nucleotide-regulatory subunit.
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PMID:[3H]WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity. 286 62

The high-affinity GTP hydrolyzing activity stimulated by 5-hydroxytryptamine (5-HT) receptor agonists was pharmacologically characterized in rat hippocampal membranes. The addition of 100 microM 5-HT increased significantly the Vmax of high-affinity GTPase activity with an apparent Km of 0.37 microM in a Mg(++)-dependent fashion. 5-HT receptor agonists, except for the selective 5-HT2 receptor agonists, (+/-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, stimulated the activity in a concentration-dependent manner, with affinities indicative of the 5-HT1A receptor involvement. 2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane, buspirone, ipsapirone, metergoline and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin showed activities characterizing these as partial agonists. The drug 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine was also characterized as a weak partial agonist. 5-HT (100 nM)-stimulated activity was potently antagonized by metitepine (also called methiothepin) and spiperone (with a Kb value of 37 nM in a competitive manner) but not by ketanserin. The affinities of the agonists obtained in this study correlated well with those for the 5-HT1A receptor-mediated inhibition of forskolin-stimulated adenylyl cyclase activity in guinea pig and rat hippocampal membranes reported in a previous article. The 5-HT-mediated activation of high-affinity GTPase in rat hippocampal membranes can be used to investigate a functional interaction between the 5-HT1A receptors and G proteins, in particular the Gi subfamily, associated with adenylyl cyclase inhibition.
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PMID:Pharmacological characterization of the 5-hydroxytryptamine-1A receptor-mediated activation of high-affinity GTP hydrolysis in rat hippocampal membranes. 761 17

BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8- azaspiro[4.5]decane-7,9-dione dihydrochloride), a 5-HT1A receptor partial agonist, also binds to alpha 1-adrenoceptors. Competition assays were performed using (+/-)-beta-([125I]iodo-4-hydroxyphenyl)-ethyl-aminomethyl-tetralone ([125I]HEAT), and membranes prepared from Rat-1 fibroblasts expressing hamster alpha 1b-, bovine alpha 1c-, or rat alpha 1d-adrenoceptor, or their respective human homologues. Results indicate that BMY 7378 is selective for the alpha 1D-adrenoceptor subtype (pKi: hamster alpha 1b-adrenoceptor 6.2 +/- 0.03, human alpha 1b-adrenoceptor 7.2 +/- 0.05; bovine alpha 1c-adrenoceptor 6.1 +/- 0.02, human alpha 1c-adrenoceptor 6.6 +/- 0.20; rat alpha 1d-adrenoceptor 8.2 +/- 0.06, human alpha 1d-adrenoceptor 9.4 +/- 0.05) and has high affinity (pA2, 8.9 +/- 0.1) for rat aorta alpha 1-adrenoceptor.
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PMID:BMY 7378 is a selective antagonist of the D subtype of alpha 1-adrenoceptors. 771 54

New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.
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PMID:Orally active benzamide antipsychotic agents with affinity for dopamine D2, serotonin 5-HT1A, and adrenergic alpha1 receptors. 962 41

A series of new N-substituted 2,3-dihydro-2-aminomethyl-2H-1-benzofuran derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, D2, and D3 receptors. Compound 9, 8-[4-[N-propyl-N-(7-hydroxy-2,3-dihydro -2H-1-benzofuran-2-yl)methyl]aminobutyl]-8-azaspiro[4,5]decane-7,9 -dione, bound at 5-HT1A sites with nanomolar affinity (IC50= 1.5 nM) and high selectivity over 5-HT2A, 5-HT2C, 5-HT3, D2, and D3 receptors.
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PMID:N,N-disubstituted aminomethyl benzofuran derivatives: synthesis and preliminary binding evaluation. 1021 26

In connection with the development of new potential 5-HT1A ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-dihydro-1,4-dioxinol[2,3-b]pyridin e derivatives as ORG13514 analogs are described. Their biological activity as 5-HT1A type ligands is reported and compared with ORG13514 affinity and selectivity for 5-HT1A receptors.
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PMID:Synthesis of various analog derivatives of ORG13514 as 5-HT1A ligands. 1066 81

A series of new 3-amino, 3-aminomethyl-5-alkoxy-3,4-dihydro-2H-1-benzopyran and 5'-alkoxy-3',4'-dihydrospiro-[piperazine-2.3'(2'H)-benzopyran] derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A and D2 receptors. Two of the compounds (1f and 2b) can be considered as potent and selective 5-HT2A ligands. One compound (1g) demonstrated high affinity for 5-HT1A and D2 receptor binding sites and one compound (1d) proved to be a mixed 5-HT1A/5-HT2A ligand.
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PMID:Substituted 3-amino and/or 3-aminomethyl-3,4-dihydro-2H-1-benzopyrans: synthesis and biological activity. 1073 64

On the basis of the affinities at the alpha1a-, alpha1b- and alpha1d-adrenoceptors and the 5-HT1A receptor of a previous series of sixteen 2-[(2-phenoxyethyl)aminomethyl]-1,4-benzodioxanes ortho monosubstituted at the phenoxy moiety, a number of ortho disubstituted analogues were designed, synthesized in both the enantiomeric forms and tested in binding assays on the same receptors. The affinity values of the new compounds 1-11 were compared with those of the enantiomers of the 2,6-dimethoxyphenoxy analogue, the well-known alpha1 antagonist WB4101, and of the ortho monosubstituted derivatives, suggesting some distinctive aspects of the interaction of the phenoxy moiety, in particular with the alpha1a-AR and the 5-HT1A receptor, of the monosubstituted and the disubstituted compounds. A classical quantitative structure-activity relationship (Hansch) analysis was applied to the whole set of the S enantiomers of the ortho mono- and disubstituted WB4101 analogues (26 compounds), finding a very good correlation for the alpha1a affinity. For this latter, a significant parabolic relationship was also found with the volume of the two ortho substituents. Diametrically opposite, the same relationships for the 5-HT1A exhibit low or insignificant correlation coefficients.
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PMID:QSAR study for a novel series of ortho disubstituted phenoxy analogues of alpha1-adrenoceptor antagonist WB4101. 1673 60