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)

The mouse black and white test box was used to measure changes in behaviour in an aversive situation where the administration of R(+)-zacopride (but not S(-)-zacopride) alone decreased aversive responding to the white area. A similar anxiolytic profile of action was observed using parachlorophenylalanine (PCPA), whose effects were antagonised by a co-treatment with R(+)-zacopride and reversed by S(-)-zacopride to an exacerbation of the aversive response. An anxiolytic profile of action was also observed using ondansetron, granisetron, chlordiazepoxide, diazepam, ritanserin, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), E4424 (2-[4-[4-(4-chloro-l-pyrazoyl)butyl]-l-piperazinyl]-pyrimidine), umepsirone, DuP753 (2-n-butyl-4-chloro-5-hydroxy-methyl-1-[2(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)]-imidazole), SQ29,852 ((S)-1-[6-amino-2[hydroxy)(4-phenyl-butyl)phosphinyl]-oxy)-1- nexy]-2-proline), devazepide and guanfacine, and this was retained following co-treatment with PCPA. The anxiolytic profile of action of PCPA was also retained following co-treatment with renzapride which when administered alone failed to modify behaviour. However, the ability of chlordiazepoxide, diazepam, ondansetron and E4424 (but not devazepide, DuP753 or SQ29,852) to reduce aversive responding was inhibited by co-treatment with R(+) and/or S(-)-zacopride. It is concluded that the reduction in aversive responding caused by pharmacological manipulation at the benzodiazepine, 5-HT receptor subtypes 5-HT1A, 5-HT1C/5-HT2 and 5-HT3 (but not at the cholecystokin CCKA or angiotensin receptors or inhibition of angiotensin converting enzyme) can be inhibited by R(+) and S(-)-zacopride. The data is discussed in terms of zacopride having an agonist or partial agonist effect at the 5-HT3 receptor.
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PMID:Profiles of interaction of R(+)/S(-)-zacopride and anxiolytic agents in a mouse model. 135 7

The 5-HT1A and 5-HT2A receptor affinity of model 1-(2-pyrimidinyl)-piperazine derivatives 15-21 and 23-32 has been determined. 2-(N-Methylpiperazino)-4,6-di(2-thienyl)pyrimidine 26 is a new, highly active and selective 5-HT2A receptor ligand. The topography of a molecule and the stereoelectronic effects of the thiophene rings are the major factors responsible for the high affinity and selectivity of 26 towards 5-HT2A sites.
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PMID:Structure-activity relationship studies of CNS agents. Part 14: Structural requirements for the 5-HT1A and 5-HT2A receptor selectivity of simple 1-(2-pyrimidinyl)piperazine derivatives. 783 64

Previous studies have shown that the 5-HT1A receptor ligand, lesopitron (E-4424, 2-[4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl]pyrimidine), exerts potent anxiolytic-like effects in rodents and monkeys (Costall et al., 1992, J. Pharmacol. Exp. Ther. 262, 90). In an attempt to determine whether these effects are really mediated through the interaction of lesopitron with central 5-HT1A receptors, we investigated the agonistic and/or antagonistic nature of this interaction under in vitro and in vivo conditions in the rat. In vitro binding and autoradiographic studies with [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT) and [3H]lesopitron as radioligands confirmed that lesopitron binds to 5-HT1A receptors in the rat brain with a relatively high affinity (pKi = 7.35). As expected of a full agonist at postsynaptic 5-HT1A receptors, lesopitron (IC50 = 125 nM) inhibited forskolin-stimulated adenylate cyclase activity in rat hippocampal membranes to the same extent as 5-HT, and this effect was preventable by potent 5-HT1A receptor antagonists such as (-)-tertatolol, (-)-propranolol and N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2-phenyl- propanamide ((+)-WAY 100135). As previously shown for agonists acting at the somato-dendritic 5-HT1A autoreceptors in the dorsal raphe nucleus, lesopitron inhibited the firing of serotoninergic neurons both in vitro (in brainstem slices, IC50 = 120 nM) and in vivo (in chloral hydrate-anaesthetized rats, ID50 = 35 micrograms/kg i.v.), and this effect was preventable by (-)-tertatolol. Interestingly, the inhibition of the discharge due to lesopitron lasted for only a few minutes both in vitro and in vivo whereas the anxiolytic-like properties of this drug lasted for hours after a single injection in mice (Costall et al., 1992). In addition, the doses required for the stimulation of pre- and postsynaptic 5-HT1A receptors were markedly higher than those producing significant anxiolytic-like effects in rodents (Costall et al., 1992). It is therefore unlikely that the anxiolytic-like properties of lesopitron involve its stimulatory action at central 5-HT1A receptors.
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PMID:Interactions of lesopitron (E-4424) with central 5-HT1A receptors: in vitro and in vivo studies in the rat. 802 43

A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the alpha 1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the best selectivity, with a ratio of 74, while its affinity IC50 for 5-HT1A was 6.8 nM. These results, compared to those for compounds 46 (IC50 24 nM; selectivity 2) and 49 (IC50 226 nM; selectivity 5), N3 unsubstituted analogues of derivatives 70 and 73, show the importance of an amino group in position 3 of the thienopyrimidine system for the interaction with 5-HT1A receptor binding sites, although this fragment can affect the affinity and selectivity only if linked to the (arylpiperazinyl)alkyl moiety. The better selectivity of piperidine 74 (IC50 0.8; selectivity 45) compared to the analogous piperazine 70 is also noteworthy. Twenty of the 30 molecules used for determining the binding affinity to 5-HT1A and alpha 1-adrenergic receptors were selected for QSAR analysis using a series of molecular descriptors and calculated with the TSAR software.
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PMID:[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands. 904 48

Simple syntheses of four new and potent analogues of the 5-HT1A receptor ligand, WAY-100635 are described, namely the 6-(pyridinyl)-bromo-, the 6-(pyridinyl)-fluoro-, the pyrimidine- and the 5-(pyridinyl)-bromo-analogues. The first three analogues were obtained by aromatic nucleophilic substitution of the 2,6-dihalogenopyridine (activated or not as an N-oxide) or of the 2-chloropyrimidine with the corresponding amine nucleophile as a key step. The fourth analogue, the 5-(pyridinyl)-bromo-analogue, was synthesized from the 2-amino-5-bromopyridine via a progressive elongation of the skeleton. The four compounds described are all full antagonists and show good in vitro binding affinities (Ki).
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PMID:Short and efficient syntheses of analogues of WAY-100635: new and potent 5-HT1A receptor antagonists. 1131 Jun 4

Synthesis applied to prepare compounds 5-15 and 17-22 discussed in this paper has been presented in Scheme 1. Multi-stage preparation techniques were used to obtain 4-aryl-hexahydro 1-4 and (R,R) and (S,S) 4-aryl-octahydropyrido[1,2-c]pyrimidine-1,3-dione (16) derivatives, being the starting compounds for further modification. N-Alkylation of the imide group in compounds 1-4 and 16 followed, using 1,4-dibromobutane to yield monobromobutyl derivatives 5-8 and 17. Subsequent condensation of those compounds with appropriate 1-aryl or 1-heteroarylpiperazine led to the final hexahydro- 9-15 and octahydro- 18-22 pyrido[1,2-c]pyrimidine-1,3-dione derivatives. The final products were subjected to screening test to elucidate the affinity to 5-HT1A and 5-HT2A receptors.
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PMID:Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. 1256 69

The preparation of new 4-aryl-hexahydropyridol 1,2-c]pyrimidine derivatives III-XXVI with an arylpiperazinylbutyl moiety in N-2 position has been described. Multi-stage synthesis techniques were used to obtain 4-arylhexahydro-1H,3H-pyrido[1,2-c]pyrimidine-1,3-dione Ia-f derivatives, being the starting compounds for further modification. N-alkylation of the imide group in compounds Ia-f followed, using 1,4-dibromobutane to yield bromobutyl derivatives IIa-f. The final products III-XXVI were obtained by condensation of aryl- or heteroaryl- piperazine with the bromobutyl derivatives IIa-f. Compounds XII, XIV, XIX, XX, XXIV-XXVI will be submitted to a pharmacological investigation for their affinity towards 5-HT1A, 5-HT2A and alpha1 adrenergic receptor, using radioligand binding assay.
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PMID:Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part III. 1549 97

A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
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PMID:New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects. 1591 1

New 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione derivatives of arylpiperazine (6-18) were prepared and evaluated in vitro for their affinity for 5-HT1A, 5-HT2A, and alpha1 receptors. The influence of ortho substitution in the phenyl ring, substitution at position 4 of the pyrido[1,2-c]pyrimidine system, and its unsaturation degree were explored. The tested compounds showed high affinity for the 5-HT1A receptor (Ki = 1.3-79.2 nM) and moderate to low affinity for the 5-HT2A (Ki = 51.7-1405 nM) and alpha1 receptors (Ki = 19.7-382.3 nM). Compounds 8 and 10 showed the highest 5-HT1A receptor affinity (Ki = 1.3 and 2.2 nM, respectively) and were 37- and 35.9-fold, respectively, more selective in relation to alpha1 adrenoreceptors.
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PMID:Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT1A and 5-HT2A receptors. Part 4. 1626 95

Structural features of the pyrido[1,2-c]pyrimidine derivatives with arylpiperazine moiety and their affinities towards 5-HT1A, 5-HT2A and alpha1-adrenergic receptors were analyzed using the CoMFA procedure. On the basis of 3D-QSAR models for the 5-HT2A and alpha1-adrenergic receptors, four compounds with expected better affinity/selectivity were proposed and synthesized. The affinities obtained confirm experimentally the usefulness of CoMFA models. Our results suggest that active conformations adopted by the studied molecules when interacting with the receptors are neutral instead of the protonated ones.
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PMID:CoMFA methodology in structure-activity analysis of hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives based on affinity towards 5-HT1A, 5-HT2A and alpha1-adrenergic receptors. 1654 63


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