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 effects of acute and repeated treatment with the 5-HT1A receptor ligand gepirone on hippocampal excitatory synaptic transmission were investigated. Recordings of the electrically evoked field population excitatory postsynaptic potentials (e.p.s.p.s) were made in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert male Wistar rats. Acute injection of gepirone reduced the e.p.s.p. amplitude in a transient dose-dependent (0.5-10 mg/kg, i.p.) manner. This effect was blocked by the 5-HT1A receptor antagonist MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethys]-8- azaspiro[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg, i.p.). Gepirone (1 mg/kg per day, i.p.) administered for 7 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a concomitant reduction of the acute response to the drug. The chronic baseline reduction was transiently reversed by the 5-HT1A receptor antagonist spiroxatrine and complete recovery to pretreatment levels was observed 48 h after the last gepirone dose. The data indicate that with repeated administration, a prolongation and enhancement of the 5-HT1A receptor-mediated reduction in the e.p.s.p. by gepirone occurs. This delayed effect may contribute to the slow onset of therapeutic action of gepirone.
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PMID:5-HT1A receptor-mediated inhibition in the hippocampus of the alert rat--effects of repeated gepirone treatment. 798 38

In vitro biochemical and electrophysiological methods were used to assess the potential antagonist properties of the novel compounds (+)-WAY 100 135 [N-tert-butyl-3,4-(2-methoxyphenyl)piperazin-1-yl-2- phenylpropanamide dihydrochloride] and SDZ 216-525 [methyl 4-(4-(4-(1,1,3-trioxo-2H-1,2-benziosothiazol-2-yl)butyl)- 1-piperazinyl)1H-indole-2-carboxylate] at pre- (i.e. somatodendritic autoreceptors) and postsynaptic 5-HT1A receptors in the rat brain. Both (+)-WAY 100 135 and SDZ 216-525 were pure antagonists at postsynaptic 5-HT1A receptors negatively coupled to adenylate cyclase in rat hippocampal membranes. Competitive prevention of the inhibition by the 5-HT1A receptor agonists 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin], 5-HT (5-hydroxytryptamine), S-20499 [(+)-4-(N-(5-methoxychroman-3-yl)-N-propylamino)butyl-8-azaspir o(4,5)decane- 7,9-dione] and lesopitron occurred with a pA2 of 8.7 for (+)-WAY 100 135 and 9.9 for SDZ 216-525. The higher potency of the latter compound was also noted at the level of presynaptic 5-HT1A receptors where both (+)-WAY 100 135 and SDZ 216-525 prevented the negative influence of 5-HT1A receptor agonists (8-OH-DPAT, flesinoxan or lesopitron) on the nerve impulse flow within dorsal raphe nucleus 5-HT neurones in brain stem slices. At high concentrations, both (+)-WAY 100 135 (> 1 microM) and SDZ 216-525 (> or = 0.1 microM) inhibited the spontaneous cell discharge through different mechanisms. The blockade of alpha 1-adrenoceptors by (+)-WAY 100 135 apparently accounted for its inhibitory influence on the firing of 5-HT neurones, whereas 5-HT1A receptor agonist properties were responsible for the effect of SDZ 216-525. Although approximately 10 times less potent than SDZ 216-525, (+)-WAY 100 135 is therefore a pure antagonist at both pre- and postsynaptic 5-HT1A receptors in the rat brain.
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PMID:Further assessment of the antagonist properties of the novel and selective 5-HT1A receptor ligands (+)-WAY 100 135 and SDZ 216-525. 828 17

The effect of the 5-HT1A receptor partial agonist tandospirone on memory was investigated in mice using a single trial, step-through passive avoidance task. Tandospirone disrupted performance in a dose-dependent manner when administered before the training trial but not when injected immediately post-training. The pre-training effect was not the result of reduced responsiveness to foot shock because tandospirone did not alter current threshold intensity to elicit flinch, run and vocalization responses. The performance deficit was alleviated by treatment with d-amphetamine prior to the retention test. The memory impairment by tandospirone was mimicked by the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-dipropylaminotetralin HBr) and blocked by the 5-HT1A receptor antagonist BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4]- decane-7,9-dione). BMY7378 alone was ineffective. Treatment with the 5-HT synthesis inhibitor PCPA (parachlorophenylalanine) resulted in apparent enhancement rather than disruption of the avoidance behavior. However, the anterograde amnestic effects of tandospirone and 8-OH-DPAT were not affected by PCPA, and lack of interactions between PCPA and the 5-HT1A agonists revealed in the statistical analyses indicated that the effects of PCPA were not mediated by 5-HT1A receptors. It is concluded that 5-HT1A receptor agonists and partial agonists produce a reversible anterograde amnesia that is mediated by postsynaptic 5-HT1A receptors.
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PMID:5-HT1A receptor agonists induce anterograde amnesia in mice through a postsynaptic mechanism. 831 49

The effects of acute and repeated treatment with 1-(2-pyrimidinyl)piperazine (1-PP), a metabolite of the 5-HT1A receptor ligand azapirones, were investigated on hippocampal excitatory synaptic transmission. Recordings of the electrically evoked field population excitatory post-synaptic potentials (e.p.s.p.s.) were carried out in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert rats. Acute i.p. administration of 1-PP transiently reduced the e.p.s.p. amplitude in a dose-dependent (0.25-1 mg/kg) manner. This effect was blocked by the 5-HT1A receptor antagonists spiroxatrine (1 mg/kg) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethyl]-8-azaspirol[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg). Intrahippocampal administration of 1-PP (5 microg) evoked a transient reduction of the e.p.s.p. amplitude which was similar to that obtained with 5-HT (10 microg). 1-PP (0.25 mg/kg per day) administered for 9 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a decrease in the acute response to the drug. The chronic baseline reduction was transiently reversed by spiroxatrine and full recovery to pretreatment levels was observed 4 days after the last 1-PP dose. These findings indicate that the previously reported reduction in the e.p.s.p. produced by the azapirone group of 5-HT1A receptor ligands may be mediated in part by their metabolite 1-PP through activation of 5-HT1A receptors.
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PMID:The azapirone metabolite 1-(2-pyrimidinyl)piperazine depresses excitatory synaptic transmission in the hippocampus of the alert rat via 5-HT1A receptors. 875 Jul 26

1. HT-90B ((-)-N-([2-(8-methyl-l, 4-benzodioxane-2-ylmethyl)amino]ethyl) tricyclo[3,3,1,1(3.7)] decane-1-carboxamide) had high affinities for the 5-HT1A (Ki = 0.18 nM) and 5-HT2 (Ki = 9.2 nM) receptors. 2. HT-90B inhibited forskolin activated adenylate cyclase in rat hippocampal membranes as a 5-HT1A full agonist (IC50 = 2 nM), and the potency of the drug was higher than that of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a standard 5-HT1A agonist. 3. In the serotonin syndrome test, HT-90B behaved as a weak partial 5-HT1A agonist in reserpinized rats. 4. 5-HT2 receptor-mediated potentiation of rabbit platelet aggregation by serotonin (5-HT) was reduced by HT-90B (IC50 = 1.73 microM). 5. Head twitch response induced by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2 agonist, was inhibited by HT-90B in mice. 6. It is concluded that HT-90B has potent 5-HT1A receptor agonist as well as 5-HT2 receptor antagonist properties in vitro and in vivo.
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PMID:Pharmacological profile of (-)HT-90B, a novel 5-HT1A receptor agonist/5-HT2 receptor antagonist. 878 43

To characterize their in vivo 5-hydroxytryptamine (5-HT)2A antagonist properties, the ability of the putative mixed 5-HT1A agonists/5-HT(2A,2C) antagonists (N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) ) decane-1-carboxamide (WY-50,324), (2-(4-(4,4-bis(4-fluorophenyl)butyl)-1-piperazinyl)-3-pyridinecarboxy lic acid hydrochloride (FG5974), 9,10-didehydro-N-(2-propynyl)-6-methylergoline-8b-carboxamid e (LEK-8804) and trans-1,3,4,a5,10b-hexahydro10-methoxy-4-propyl-2H-(1)benzopyra nol[3,4-b]pyridine (CGS 18102A) to antagonize both head twitches and discriminative stimulus (DS) effects produced by (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) in rats were compared with those of the 5-HT2 antagonists ketanserin and ritanserin, and the 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone. All of these compounds produced dose-related decreases in DOI-induced head twitches; however pretreatment with the 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635) failed to alter the ability of ritanserin, ketanserin or CGS 18102A to attenuate DOI-induced head twitches. In contrast, WAY-100635 completely blocked the effects of 8-OH-DPAT, buspirone and WY-50,324, and partially blocked the effects of LEK-8804, demonstrating that 5-HT1A agonist properties are involved in the effects of all of the mixed compounds except CGS 18102A. In rats trained to discriminate DOI (0.63 mg/kg) from saline in a two-lever, FR10 drug discrimination paradigm, ketanserin, ritanserin and CGS 18102A blocked the DS effects of the training dose by more than 50%. In contrast, WY-50,324, FG5974, LEK-8804, buspirone and 8-OH-DPAT, up to doses that completely suppressed responding, failed to produce more than a 33% blockade of the DS effects of DOI. In vivo 5-HT1A agonist effects were demonstrated by the finding that relatively selective- and mixed-5-HT1A agonists produced one or more elements of the "serotonin syndrome," i.e., flat-body posture, forepaw treading, or lower-lip retraction, and produced high levels of drug-lever selection in rats trained to discriminate 8-OH-DPAT (0.16 mg/kg) from saline. Because DOI-induced head twitches and DS effects are thought to be mediated by 5-HT2A receptors, the results demonstrate that the putative mixed compound, CGS 18102A has prominent 5-HT2A antagonist properties in vivo, whereas 5-HT2A antagonist effects of WY-50,324, FG5974 and LEK-8804 could not be clearly identified.
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PMID:Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT(2A/2C) antagonist anxiolytics. II. Drug discrimination and behavioral observation studies in rats. 926 38

Determination of the optimal assay conditions for the specific binding of a tritiated derivative of the novel potential anxiolytic drug alnespirone (S-20499, (+)-4-[N-(5-methoxy-chroman-3-yl)-N-propylamino]butyl-8-azaspiro-( 4,5)-decane-7,9-dione) allowed the demonstration that this radioligand bound with a high affinity (Kd = 0.36 nM) to a homogeneous class of sites in rat hippocampal membranes. The pharmacological properties of [3H]alnespirone specific binding sites matched exactly (r = 0.95) those of 5-HT1A receptors identified with [3H]8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as radioligand. Furthermore, membrane binding experiments and autoradiographic labeling of tissue sections showed that the regional distribution of [3H]alnespirone specific binding sites in the rat brain and spinal cord superimposed over that of 5-HT1A receptors specifically labeled by [3H]8-OH-DPAT. However, the differential sensitivity of [3H]alnespirone and [3H]8-OH-DPAT specific binding to various physicochemical effectors (temperature, pH, Mn2+, N-ethyl-maleimide) supports the idea that these two agonist radioligands did not recognize 5-HT1A receptors exactly in the same way. These differences probably account for the reported inability of alnespirone, in contrast to 8-OH-DPAT, to induce some 5-HT1A receptor-mediated behavioural effects in rats.
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PMID:[3H]Alnespirone: a novel specific radioligand of 5-HT1A receptors in the rat brain. 943 Apr 29

Continuing our studies connected with the design of new anxiolytics we have now synthesized a series of new compounds, derivatives of 7,8-benzo-1,3-diazaspiro[4,5]decane-2,4-dione bearing a 4-aryl-1-piperazinylbutyl group attached to the imide nitrogen. One single compound was submitted to the 5-HT1A receptor binding assay and found to display the expected--though rather weak--receptorial affinity.
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PMID:Synthesis of N-(4-aryl-1-piperazinylbutyl)-substituted 7,8-benzo-1,3-diazaspiro[4,5]decane-2,4-dione derivatives with potential anxiolytic activity. 960 24

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

5-HT(1B/D) receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)-H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide ) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT(1B/D) receptor agonists in the guinea pig. Previous studies have shown that 5-HT1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT(1B/D) receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT1A and 5-HT(1B/D) receptor stimulation on locomotor activity in that species. The full agonist at 5-HT1A receptors, 8-OH-DPAT (R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3-1.25 mg kg(-1) s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5 ]decane-7,9-dione HCl) (5.0-20.0 mg kg(-1) s.c.). The 5-HT(1B/D) receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg(-1) s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT1A receptor antagonist WAY100635 (N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg(-1), but not by the 5-HT(1B/D) receptor antagonist GR127935 (2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-amide) (0.25-1.0 mg kg(-1)). GR46611, at doses that were without effect given alone (0.5-2.5 mg kg(-1)), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg(-1)) and buspirone (10 mg kg(-1)). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT(1B/D) receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT1A receptor stimulation in guinea pigs.
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PMID:GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig. 1032 55


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