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)

A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A against 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D2, and D3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.
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PMID:Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 1. Effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes. 778 52

A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a Ki of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.
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PMID:Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 2. Effects of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology. 778 53

The partial DA receptor agonist preclamol, (-)-3-PPP (50-200 mumol/kg, s.c.) partially reversed the catalepsy induced by the dopamine (DA) receptor antagonists haloperidol (5.3 mumol/kg, i.p.) and raclopride (20.1 mumol/kg, i.p.) in rats. Terguride (transdihydrolisuride), a partial DA receptor agonist with an efficacy lower than that of preclamol, blocked haloperidol (10.6 mumol/kg, i.p.) induced catalepsy at 5 mumol/kg, s.c., but not at 20 mumol/kg, s.c. The effects of terguride in this assay are possibly related to the compound's mixed partial DA agonist/5-HT1A receptor agonist properties. The high efficacy agonist, pramipexole (SND 919) also blocked haloperidol induced catalepsy at 50 mumol/kg, s.c. Haloperidol (0.33-1.3 mumol/kg, i.p.) reduced the locomotor activity down to 5% of saline controls and elevated limbic and striatal DOPA accumulation. When combined with haloperidol, preclamol (100-200 mumol/kg, s.c.) antagonized both the strong hypomotility and increase in DOPA accumulation. Finally, the elevation of serum prolactin in rats induced by haloperidol (0.25 mumol/kg, i.p.) was significantly antagonized by co-administration of preclamol (39 mumol/kg, s.c.). These results show that partial DA agonists can reverse both behavioral, biochemical and neuroendocrine effects of neuroleptics. It also suggests the utility of partial DA receptor agonists in combination with classical neuroleptics in order to minimize the appearance of extrapyramidal side-effects and hyperprolactinemia.
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PMID:Partial dopamine receptor agonists reverse behavioral, biochemical and neuroendocrine effects of neuroleptics in the rat: potential treatment of extrapyramidal side effects. 790 92

The effects of the 5-HT1A receptor agonists 8-OH-DPAT (0.15-2.5 mumol kg-1 subcutaneously), flesinoxan (0.6-10.0 mumol kg-1 subcutaneously) and buspirone (1.9-30.0 mumol kg-1 subcutaneously) on spontaneous motor activity in male Sprague-Dawley rats was examined in a photocell-equipped open-field arena. Following motor activity observations, the cerebral aromatic L-amino acid decarboxylase inhibitor NSD-1015 (100 mg kg-1 intraperitoneally) was administered and 30 min. later the animals were decapitated for subsequent analysis of the accumulated forebrain DOPA and 5-HTP levels, as an estimate of the rate of monoamine synthesis. 8-OH-DPAT and flesinoxan produced a similar and characteristic pattern of changes of the spontaneous motor activity in normal animals i.e. a moderate decrease in locomotor activity, a marked suppression of rearing and an increase in the relative amount of forward locomotion and of activity in the periphery of the open-field arena. This behavioural profile was closely related to a decrease in forebrain 5-HTP accumulation, indicating 5-HT receptor stimulation. In agreement with these observations buspirone also produced an increase in peripheral activity and a suppression of rearing. In contrast to effects by 8-OH-DPAT and flesinoxan, however, buspirone produced a further reduction of locomotor activity and reduced the forward locomotion. This difference in behavioural profile between buspirone and the other two compounds is probably explained by its DA receptor blocking properties, as indicated by an increased DOPA accumulation in the neostriatum. At least partially, 8-OH-DPAT, flesinoxan and buspirone, all antagonized reserpine-induced (5 mg kg-1 subcutaneously--16 hr) suppression of locomotor activity. This stimulation of locomotor activity in reserpine-treated rats is in all probability related to 5-HT1A receptor stimulation since concomitant DA D2 receptor blockade, in the case of buspirone, did not markedly affect this behavioural response.
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PMID:Effects of 5-HT1A receptor agonists on patterns of rat motor activity in relation to effects on forebrain monoamine synthesis. 836 51

The medial zona incerta (MZI) and dorsomedial nucleus of the hypothalamus (DMN), which contain cell bodies and terminals of incertohypothalamic dopaminergic (DA) neurons, are densely innervated by both noradrenergic (NE) and 5-hydroxytryptaminergic (5-HT) neurons. In view of emerging anatomical and pharmacological evidence suggesting possible interactions between 5-HT and catecholaminergic neurons, the effects of experimental procedures that inhibit or disrupt 5-HT neurons on the activities of catecholaminergic neurons terminating in these regions were examined in the present study. Catecholaminergic neuronal activity was estimated by measuring catecholamine synthesis (accumulation of 3,4-dihydroxyphenylalanine [DOPA] after administration of a decarboxylase inhibitor) and metabolism (concentrations of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG)) in the MZI and DMN of both male and female rats. Inhibition of 5-HT neurons following administration of the 5-HT1A autoreceptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the accumulation of DOPA in the DMN and the concentrations of DOPAC in the MZI and DMN, indicating an activation of catecholaminergic neurons in these regions. Concentrations of MHPG were increased in the MZI and DMN by 8-OH-DPAT or 5,7-dihydroxytryptamine-induced lesions of 5-HT neurons, revealing that NE neurons terminating in these regions were activated following procedures that decrease 5-HT neuronal function. Following destruction of NE neurons projecting to the MZI and DMN, 8-OH-DPAT no longer increased DOPAC concentrations in these brain regions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurochemical evidence that 5-hydroxytryptaminergic neurons tonically inhibit noradrenergic neurons terminating in the hypothalamus. 848 97

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows that s.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.
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PMID:Differential serotoninergic and dopaminergic activities of the (R)- and the (S)-enantiomers of 2-(di-n-propylamino)tetralin. 881 61

The receptor-mediated control of brain monoamine synthesis was used to examine the in vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-299, S(-)-UH-301 and WAY-100,635. The rate of monoamine synthesis was estimated by measuring the accumulation of DOPA and 5-HTP in the ventral neostriatum and the ventral hippocampus in rats pretreated with an inhibitor of cerebral aromatic L-amino acid decarboxylase. S(-)-UH-301 (2.0-32.0 micromol kg(-1)), but not WAY-100,635 (0.08-1.2 micromol kg(-1)), produced a decreased 5-HTP accumulation in the neostriatum and in the hippocampus. The administration of NAD-299 (0.75-12.0 micromol kg(-1)) resulted in a slight increase in neostriatal, but not hippocampal, 5-HTP accumulation. Neostriatal DOPA accumulation was decreased by S(-)-UH-301, whereas treatment with WAY- 100,635 resulted in an increase. NAD-299 did not affect neostriatal DOPA levels. There were no effects by any of these agents on DOPA levels in the ventral hippocampus. It is concluded that S(-)-UH-301, but not WAY-100,635 or NAD-299, displays intrinsic efficacy at brain 5-HT1A and DA D2/3 receptors, whereas WAY-100,635 behaves as a DA D2/3 receptor antagonist. By this comparison, NAD-299 appears to be the most selective and specific 5-HT1A receptor antagonist.
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PMID:In vivo intrinsic efficacy of the 5-HT1A receptor antagonists NAD-299, WAY-100,635 and (S)-(-)-UH-301 at rat brain monoamine receptors. 1008 23

This study was designed to assess the effects of imidazoline drugs on putative presynaptic imidazoline receptors modulating brain monoamine synthesis in vivo. The accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of the rate of tyrosine and tryptophan hydroxylation in various brain regions of naive rats and after irreversible alpha2-adrenoceptor inactivation with EEDQ (1.6 mg/kg, i.p., 6 h). Clonidine (1-3 mg/kg), moxonidine (1-10 mg/kg) and rilmenidine (10 mg/kg) (mixed I1/alpha2 agonists) decreased dopa and 5-HTP synthesis in the cerebral cortex (14%-81%), hippocampus (27%-84%) and/or striatum (29%-56%), but these inhibitory effects were abolished in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Similarly, the stimulatory effect of efaroxan (mixed I1/alpha2 antagonist; 10 mg/kg) on dopa synthesis in the cortex (77%) and hippocampus (57%) was abolished by EEDQ. The selective I1-ligand 2-endo-amino-3-exoisopropylbicyclo-heptane (AGN-192403; 5-10 mg/kg) did not modify dopa or 5-HTP synthesis in any brain region in naive or EEDQ-treated rats. Idazoxan (mixed I2/alpha2 antagonist; 20 mg/kg) increased dopa synthesis in the cortex (111%) and hippocampus (87%), but the stimulatory effects were abolished by EEDQ. Moreover, idazoxan and efaroxan decreased 5-HTP synthesis in the cortex (12%-34%) and hippocampus (30%-34%) in a manner sensitive to blockade by the 5-HT1A receptor antagonist WAY 100135. The selective I2-igands 2-(2-benzofuranyl)-2-imidazoline (2-BFI; 20 mg/kg) and 2-styryl-2-imidazoline (LSL 61122; 10 mg/kg) did not alter the synthesis of dopa or 5-HTP in the cortex or hippocampus. In striatum, 2-BFI (1-20 mg/kg) dose-dependently decreased dopa synthesis (ED50: 5.9 mg/kg), reduced dopamine levels (6%-36%) and increased those of its metabolites DOPAC (15%-95%) and HVA (24%-74%). The inhibitory effect of 2-BFI on dopa/dopamine synthesis in striatum remained unchanged after alkylation of imidazoline receptors with isothiocyanatobenzyl imidazoline (IBI; 60 mg/kg, 6 h) or blockade of these receptors with 2-(2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole (KU-14R; 7-20 mg/kg). Therefore, most imidazoline drugs modulated the synthesis of brain monoamines through interaction with alpha2-adrenoceptors or 5-HT1A receptors. The results do not provide functional evidence for the existence of presynaptic imidazoline receptors regulating the synthesis of monoamines in the rat brain.
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PMID:Effects of imidazoline receptor ligands on monoamine synthesis in the rat brain in vivo. 1046 34

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.
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PMID:Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo. 1049 82

We investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on L-DOPA-derived extracellular dopamine (DA) levels in the striatum of rats with nigrostriatal dopaminergic denervation using in vivo microdialysis. Treatment with fluoxetine (10 mg/kg, i.p.) induced a 41% reduction in the cumulative amount of extracellular DA during 300 min following L-DOPA administration (50 mg/kg, i.p.; p < 0.01). This effect was antagonized by pretreatment with WAY-100635, a potent 5-HT1A antagonist, indicating that this effect of fluoxetine is due to its indirect 5-HT1A agonistic property. These results suggest that SSRIs may impair motor functions in patients with Parkinson's disease by reducing efflux of exogenous L-DOPA-derived DA.
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PMID:Fluoxetine reduces L-DOPA-derived extracellular DA in the 6-OHDA-lesioned rat striatum. 1133 77


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