UNIPROT:P08908 - FACTA Search

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)

(R,S)-trans-8-Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'- propenyl)amino]tetralin 7, a new radioiodinated ligand based on 8-OH-DPAT, was reported as a potential ligand for 5-HT1A receptors. The optically active (+)-(R)- and (-)-(S)-7 were prepared to investigate the stereoselectivity of (R,S)-7. Racemic intermediate 8-methoxy-2-N-n-propyltetralin was reacted with the acyl chloride of (-)-(R)-O-methylmandelic acid to form a mixture of (S,R)- and (R,R)-diastereoisomers, which were separated by flash column chromatography. After removing the N-acyl group from the diastereoisomers, the desired (+)-(R)- or (-)-(S)-7 was obtained by adding an N-iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5-HT1A receptors. (+)-(R)-7 isomer displayed 100-fold higher affinity than the (-)-(S)-7 isomer. Biochemical study indicated that (+)-(R)-7 potently inhibited forskolin-stimulated adenylyl cyclase activity in hippocampal membranes (Emax and EC50 were 24.5% and 5.4 nM, respectively), while (-)-(S)-7 showed no effect at 1 microM. The radioiodinated (+)-(R)- and (-)-(S)-[125I]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP-1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)-(R)-[125I]7, displayed high binding affinity to 5-HT1A receptors (Kd = 0.09 +/- 0.02 nM). In contrast, the (-)-(S)-7 isomer displayed a significantly lower affinity to the 5-HT1A receptor (Kd > 10 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis of (+)-(R)- and (-)-(S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)] aminotetralin: new 5-HT1A receptor ligands. 757 52

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

The effects of sub-chronic cold stress on the functioning of hippocampal 5-HT1A receptors in old isolated rats and the possible protective effects of Ginkgo biloba extract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [3H]8-OH-DPAT binding sites were affected indicating that the reduced sensitivity of 5-HT1A receptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress-induced desensitization of 5-HT1A receptors was prevented by the administration of EGb 761 (50 mg/kg per os/14 days). These results clearly indicate that 5-HT1A receptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age-related decreased capacity to adapt to a chronic stressor.
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PMID:Stress-induced 5-HT1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761). 762 30

We have used the polymerase chain reaction technique to selectively amplify a guanine nucleotide-binding protein-coupled receptor cDNA sequence from rat striatal mRNA that exhibits high homology to previously cloned serotonin receptors. Sequencing of a full length clone isolated from a rat striatal cDNA library revealed an open reading frame of 1311 base pairs, encoding a 437-residue protein with seven hydrophobic regions. Within these hydrophobic regions, this receptor was found to be 41-36% identical to the following serotonin [5-hydroxytryptamine (5-HT)] receptors: 5-HT2 > 5-HT1D > 5-HT1C > 5-HT1B > 5-HT1A > 5-HT1E. Northern blots revealed a approximately 4.2-kilobase transcript localized in various brain regions, with the following rank order of abundance: striatum >> olfactory tubercle > cerebral cortex > hippocampus. Expression of this clone in COS-7 cells resulted in the appearance of high affinity, saturable binding of (+)-[2-125I] iodolysergic acid diethylamide ([125I]LSD) with a Kd of 1.26 nM. Among endogenous biogenic amines, only 5-HT completely inhibited [125I]LSD binding (Ki = 150 nM). The inhibition of [125I]LSD binding by other serotonergic agonists and antagonists revealed a pharmacological profile that does not correlate with that of any previously described serotonin receptor subtype. In addition, this receptor exhibits high affinity for a number of tricyclic antipsychotic and antidepressant drugs, including clozapine, amoxipine, and amitriptyline. In HEK-293 cells stably transfected with this receptor, serotonin elicits a potent stimulation of adenylyl cyclase activity, which is blocked by antipsychotic and antidepressant drugs. The distinct structural and pharmacological properties of this receptor site indicate that it represents a completely novel subtype of serotonin receptor. Based on its affinity for tricyclic psychotropic drugs and its localization to limbic and cortical regions of the brain, it is likely that this receptor may play a role in several neuropsychiatric disorders that involve serotonergic systems.
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PMID:Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. 768 Jul 51

Protein kinase C has been previously shown both to phosphorylate and to desensitize the ability of the human 5-HT1A receptor to inhibit adenylyl cyclase [Raymond, J. R. (1991) J. Biol. Chem. 266, 14747-14753]. In this study, we examined the effects of short-term treatment with protein kinase A activators on coupling to the inhibition of adenylyl cyclase and on phosphorylation of the human serotonin 5-HT1A receptor in CHO cells that stably express 1200 fmol of receptor/mg of protein. Forskolin induced a concentration- and time-dependent phosphorylation of the receptor that was detectable at 5 min and maximal at 15-30 min with a half-maximal concentration of 10-20 microM. Phosphorylation was also induced by Sp-cAMPS or dibutyryl-cAMP, and blocked by Rp-cAMPS and a pseudosubstrate inhibitor of PKA, but not by heparin (inhibitor of receptor kinase) or sphingosine (inhibitor of PKC). The stoichiometry of phosphorylation induced by forskolin was 1 mol of phosphate per mole of receptor. PKA activators did not induce a measurable desensitization of 5-HT1A receptor-inhibited adenylyl cyclase activity. However, forskolin augmented the desensitization caused by a submaximal concentration of phorbol 12-myristate 13-acetate (300 nM PMA) as evidenced by a rightward shift of the concentration-response curve for 5-HT, and approximately doubled the amount of phosphate incorporated into the receptor by PMA. Forskolin did not augment desensitization or increase the degree of phosphorylation induced by a maximal concentration of PMA (5 microM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase A induces phosphorylation of the human 5-HT1A receptor and augments its desensitization by protein kinase C in CHO-K1 cells. 772 77

5-HT1a receptors in the hippocampus play a critical role in modulating limbic system output. The activity and level of 5-HT1a receptors are modulated by glucocorticoid levels. The present study was undertaken to test the hypothesis that glucocorticoids attenuate the transcriptional activity of the 5-HT1a receptor gene. Using in situ hybridization and RNase protection assays, we observed a substantial increase in 5-HT1a mRNA expression after adrenalectomy in the same hippocampal regions in which 5-HT1a binding sites are increased. This increase in 5-HT1a mRNA expression occurs as early as 1 h after adrenalectomy and precedes the increase in receptor binding sites. Further in situ hybridization analysis showed that 5-HT1a mRNA is increased within individual hippocampal cells after adrenalectomy. Administration of dexamethasone completely prevents the adrenalectomy-induced elevation in hippocampal 5-HT1a receptor mRNA. Nuclear run-on assays showed that the rate of transcription of 5-HT1a mRNA after adrenalectomy increased 70% above the rate from control preparations and could be reduced to basal levels by the administration of dexamethasone. Adrenalectomy did not cause an increase in functional coupling of 5-HT1a receptors to adenylyl cyclase or phospholipase C. These results suggest that transcription of hippocampal 5-HT1a receptor mRNA is under negative regulation by corticosteroid hormones.
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PMID:Transcriptional regulation of hippocampal 5-HT1a receptors by corticosteroid hormones. 776 98

This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) > or = 5-methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (< 5). Maximal stimulation by 5-HT averaged 35 pmol cyclic AMP/min/mg protein over a basal activity of 159 pmol cyclic AMP/min/mg protein. 5-Methoxytryptamine and 5-carboxamidotryptamine had similar efficacies to that of 5-HT, whereas sumatriptan was about half efficacious. Other compounds known as agonists at some 5-HT receptors were weakly potent (mean pEC50 values < 5). They include the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT4 receptor agonist, renzapride and the 5-HT2 receptor agonist, (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane) (DOI). In antagonist studies, methiothepin (0.1 and 1 mumol/l) shifted the 5-HT curve to the right with no depression of the Emax, yielding pKB values of 7.4-8.0. Clozapine (1 mumol/l) also produced surmountable antagonism of 5-HT-induced effects (pKB 6.9). Ketanserin (10 mumol/l) weakly antagonized 5-HT (pKB 5.0). The 5-HT4 receptor antagonists, tropisetron (ICS 205-930) and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester), each at 1 mumol/l, did not significantly alter the concentration-response curve of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes. 784 73

A potential 5-HT1A receptor antagonist, p-MPPI, 4-(2'-methoxy-)phenyl-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido-]ethy l- piperazine, was developed. The [125I]p-MPPI demonstrated high affinity and selectivity toward 5-HT1A receptors; Kd = 0.36 nM and Bmax = 264 fmol/mg of protein in rat hippocampal membrane homogenates. The binding is not sensitive to GTP (300 microM) or Gpp(NH)p (100 microM). In forskolin-stimulated adenylyl cyclase assay using rat hippocampus, p-MPPI (up to 10 microM) showed no agonist activity as compared to that of (+/-)-8-OH-DPAT. At 100 nM it completely antagonized the inhibition of forskolin-stimulated adenylyl cyclase activity produced by 100 nM of (+/-)-8-OH-DPAT. This potential 5-HT1A antagonist may provide a powerful tool for studies of the pharmacology of the 5-HT1A receptor system.
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PMID:A potential 5-HT1A receptor antagonist: p-MPPI. 796 12

The mixed inhibitory and excitatory effects of 5-HT on hippocampal pyramidal cells were studied on hippocampal slices perfused with a low-Ca2+/high Mg2+ solution that blocked synaptic activity and induced spontaneous pyramidal cell discharge. Extracellular recordings of the spontaneous discharge revealed that, in 65% of the cells, 5-HT (0.5-10 microM) initially inhibited and then, upon washout, facilitated spontaneous discharge. Sometimes the off-stimulation persisted for the duration of the experiment. In 17% of the cells the response to 5-HT was only stimulatory, and in 15% the response was exclusively inhibitory. The 5-HT1 agonists, 8-hydroxy-dipropylamino-tetraline, and 5-carboxamidotryptamine produced inhibition with no excitatory responses upon washout. The inhibition was blocked by spiroxatrine indicating it was mediated by 5-HT1A receptors. The 5-HT3 agonist, 2-methyl 5-HT, had no effect, and the 5-HT2 antagonist, ketanserin, did not alter the excitatory responses to 5-HT. This indicates the excitatory response is not mediated by 5-HT2 or 3 receptors. Cisapride, a 5-HT4 agonist increased pyramidal cell discharge. The 5-HT3 & 4 antagonist, ICS 205-930 antagonized the excitatory responses to 5-HT, alpha-methyl 5-HT, and cisapride, indicating the excitatory response is mediated, in part, by 5-HT4 receptors. The phosphodiesterase inhibitor, isobutyl-methyl-xanthine, stimulated pyramidal cell discharge and potentiated the response to cisapride. This further suggests 5-HT4 receptor involvement since these receptors are positively coupled to adenylyl cyclase.
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PMID:5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. 798 94

1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices. 4. The excellent agreement observed for L-694,247 between the 5-HTlD radioligand binding affinity and the functional potency confirm that the two functional models (the inhibition of forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra and the inhibition of K+-evoked [3H]-5-HT release from guinea-pig frontal cortex) do indeed reflect 5-HTID-mediated events.5. L-694,247 is a novel, highly potent 5-HTID/5-HTIB receptor ligand which should prove useful for the exploration of the physiological role of these receptors in animals.
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PMID:L-694,247: a potent 5-HT1D receptor agonist. 829 8

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