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)

Ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenylpiperazine (MCPP) blocked conditioned avoidance responding (CAR) in the rat (ED50 values = 5.6 (4.6, 7.3) and 2.4 (1.9, 2.9) mg/kg i.p. (95% confidence limits), respectively) without markedly altering escape responding. Since this test predicts antipsychotic efficacy, the piperazines were examined in radioligand binding assays and found to have no affinity for dopamine (DA) binding sites, but were active at serotonin binding sites. OMPP displaced ligands for the 5-HT1A binding site with high affinity (Ki = 9.5 (5.4, 17.9) nM) but was inactive at 5-HT2 sites (Ki greater than 1000 nM). MCPP, on the other hand, displaced ligands for 5-HT1, 5-HT1A and 5-HT2 binding sites with similar potencies (Ki values = 25 (3, 67), 23 (14, 40) and 40 (33, 48) nM, respectively). Pretreatment with metergoline (1.0 mg/kg i.p. -30 min) reduced MCPP- but not OMPP-induced block of CAR. OMPP, on the other hand, acted as a DA receptor antagonist in vivo blocking amphetamine-induced stereotyped behavior, whereas MCPP did not. Neither produced catalepsy even given in doses 8-10 times those required to block CAR. Insofar as these compounds lack antidopaminergic activity in vivo, yet are active in a test (CAR) predictive of antipsychotic activity in which DA receptor antagonists are active, they may be novel antipsychotic agents, or, perhaps, false positives in the CAR paradigm.
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PMID:Block of conditioned avoidance responding in the rat by substituted phenylpiperazines. 324 Jul 68

S33005 displayed marked affinity for native, rat, and cloned human serotonin (5-HT) transporters (SERT) and less pronounced affinity for norepinephrine (NE) transporters (NET), while its affinity at dopamine (DA) transporters and >50 other sites was negligible. Reuptake of 5-HT and (less potently) NE into cerebral synaptosomes was inhibited by S33005, whereas DA reuptake was little affected. In vivo, S33005 prevented depletion of cerebral pools of 5-HT by parachloroamphetamine. Furthermore, it decreased electrical activity of raphe-localized serotonergic neurones, an action abolished by the 5-HT1A antagonist WAY100,635. At higher doses, S33005 blocked firing of locus ceruleus-localized adrenergic neurones, an action abolished by the alpha2-adrenergic antagonist idazoxan. In contrast, S33005 did not inhibit ventrotegmental dopaminergic neurones. In frontal cortex of freely moving rats, S33005 dose dependently elevated dialysate levels of 5-HT, NE, and DA. In hippocampus, levels of 5-HT and NE were similarly elevated, while in nucleus accumbens and striatum, levels of 5-HT were increased whereas DA was unaffected. Upon chronic (2 weeks) administration, basal levels of NE were elevated in frontal cortex and, therein, 5-HT2A receptor density was decreased. Comparative studies with clinically used antidepressants showed that venlafaxine possessed a profile similar to S33005 but was less potent. Clomipramine likewise interacted with SERTs and NETs but also with several other receptors types, while citalopram and reboxetine were preferential ligands of SERTs and NETs, respectively. In conclusion, S33005 interacts potently with SERTs and, less markedly, with NETs. It enhances extracellular levels of 5-HT and NE throughout corticolimbic structures and selectively elevates dialysis levels of DA in frontal cortex versus subcortical regions.
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PMID:S33005, a novel ligand at both serotonin and norepinephrine transporters: I. Receptor binding, electrophysiological, and neurochemical profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine. 1145 18