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 novel, potential anxiolytic, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine), is an agonist and antagonist (weak partial agonist) at pre- and postsynaptic serotonin (5-HT)1A receptors, respectively. Herein, we characterized its influence on dialysate levels of 5-HT, dopamine (DA) and NAD simultaneously determined in single samples of the frontal cortex (FCX) of freely moving rats, and compared its activity in several other models of potential antidepressant (AD) properties with those of the 5-HT reuptake inhibitor (SSRI), fluoxetine. S 15535 displayed high affinity at cloned human (h) 5-HT1A receptors (Ki = 0.7 nM) and >250-fold lower affinity at cloned hD2 (400 nM), hD3 (248 nM) and h alpha2A-adrenergic (AR) (190 nM) receptors. S 15535 (0.08-5.0 mg/kg s.c.) markedly and dose-dependently suppressed dialysate levels of 5-HT in the FCX, nucleus accumbens and striatum of freely moving rats, whereas fluoxetine (10.0 mg/kg s.c.) elevated levels of 5-HT in each structure. In contrast to 5-HT, dialysate levels of DA and NAD in the FCX were dose-dependently increased by S 15535, and this effect was mimicked by fluoxetine. The influence of S 15535 and fluoxetine on FCX levels of DA was regionally specific inasmuch as dialysate levels of DA in the accumbens and striatum were not modified. The selective 5-HT1A antagonist, WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (0.16) transiently elicited a slight increase in cortical levels of 5-HT, an action opposite to that of S 15535. Further, in the presence of WAY 100,635 (0.16), the influence of S 15535 (0.63) on cortical levels of 5-HT, DA and NAD was markedly attenuated. Upon chronic administration of S 15535 or fluoxetine (10.0 mg/kg s.c. daily for 14 days, in each case), there was no significant alteration in the density of beta-AR receptors in the FCX. However, in contrast to fluoxetine, S 15535 elicited a significant (25%) decrease in the density (Bmax) of 5-HT2A receptors labeled by [3H]ketanserin in the cortex; there was no alteration in Kd. In a learned helplessness paradigm in rats, S 15535 (0.63-40.0 mg/kg p.o.) markedly reduced escape deficits on each of three consecutive days of testing. Fluoxetine (2.0-8.0 mg/kg i.p.) was also active in each session, but presented a biphasic dose-response curve. Finally, under the conditions used, neither S 15535 (0.63-10.0) nor fluoxetine (0.63-10.0) decreased immobility time in the forced swim test. In conclusion, S 15535 is a selective ligand of cloned, h5-HT1A receptors. Its agonist actions at 5-HT1A autoreceptors underlie its ability to decrease extracellular levels of 5-HT in the FCX, and likely contribute to the increase in extracellular levels of DA and NAD evoked by S 15535 in this structure. Further, S 15535 is active in several other, although not all, models of potential AD activity. Thus, although S 15535 is under development as an anxiolytic agent, a further characterization of its putative AD actions would be of interest.
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PMID:S 15535, a novel benzodioxopiperazine ligand of serotonin (5-HT)1A receptors: I. Interaction with cloned human (h)5-HT1A, dopamine hD2/hD3 and h alpha2A-adrenergic receptors in relation to modulation of cortical monoamine release and activity in models of potential antidepressant activity. 922 49

The in vivo labelling of 5-hydroxytryptamine (5-HT)1A receptors in the mouse brain was studied with the novel selective 5-HT1A receptor antagonist, NAD-299 ((R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran- 5-carboxamide hydrogen (2R,3R)-tartrate monohydrate). 3H-NAD-299 was injected in a tail vein and the radioactivity in various brain regions was determined. More than 90% of the radioactivity in hippocampus, 15 min after the injection, was intact NAD-299. At this time the amount of 3H-NAD-299 was highest in hippocampus followed by frontal cortex, mesencephalon, hypothalamus, striatum and cerebellum. The specific accumulation of radioactivity (after subtracting cerebellum values) in frontal cortex and hippocampus was maximal 10 to 30 min after the injection and had almost disappeared after 2 h. Saturation kinetics derived Bmax (pmol/g wet weight tissue) values of 19.6+/-2.0 in frontal cortex and 38.0+/-3.5 in hippocampus. The apparent Kd values expressed in nmol/kg 3H-NAD-299 injected, were 12.3+/-2.2 in frontal cortex and 20.3+/-3.1 in hippocampus. The 5-HT1A receptor antagonist, WAY-100,635 competitively inhibited the specific accumulation of 3H-NAD-299 and was about equipotent with unlabelled NAD-299 with ED50 values of 20-30 nmol/kg s.c. These compounds were about 10 times more potent than the 5-HT1A receptor antagonists, p-MPPI and NDL-249 and 100 times more potent than (S)-UH-301. 5-HT1A receptor agonists, e.g. 8-OH-DPAT and flesinoxan and partial agonists, e.g. pindolol, buspirone and ipsapirone had low potency in this in vivo assay. Spiperone and methiothepin inhibited the 3H-NAD-299 accumulation at 10 micromol/kg s.c. The alpha1-adrenoceptor antagonist, prazosin at 2 micromol/kg s.c. increased significantly the specific accumulation of 3H-NAD-299. Pretreatment of the mice with the non-selective, irreversible receptor antagonist, EEDQ produced a dose related long-lasting decrease in the accumulation of 3H-NAD-299. It is concluded that NAD-299 is a very suitable ligand for studies of 5-HT1A receptors in the brain in vivo.
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PMID:In vivo labelling of the mouse brain 5-hydroxytryptamine1A receptor with the novel selective antagonist 3H-NAD-299. 965 Aug 1

The effects of two 5-HT1A receptor antagonists, (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2 H-1-benzopyran-5-carboxamide hydrogen (2 R,3 R)-tartrate monohydrate (NAD-299) and N-(2-(1-(2-methoxyphenyl)-piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride (WAY-100635) on the decrease in 5-hydroxytryptophan (5-HTP) accumulation evoked by (RS)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT) in rats treated with the decarboxylase inhibitor, 3-hydroxyphenylhydrazine (NSD 1015) were studied in four rat brain regions: hippocampus, hypothalamus, striatum and frontal cortex. Dose-response studies revealed differential effects of both antagonists in the areas examined. Both antagonists were significantly more potent in antagonising the effect of 0.30 and 0.76 micromol/kg s.c. 8-OH-DPAT in hippocampus than in hypothalamus, striatum and frontal cortex in mentioned order. This order of potency was the opposite to that found for 8-OH-DPAT in decreasing the 5-HTP accumulation. Since previous studies by others have indicated that the reserve of somatodendritic 5-HT1A receptors is greater in dorsal raphe nucleus innervating frontal cortex and striatum than in median raphe nucleus which mainly innervates hippocampus, the observed different regional potency of the two 5-HT1A receptor antagonists may be explained by this difference in the 5-HT1A receptor reserve.
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PMID:Differential regional antagonism of 8-OH-DPAT-induced decrease in serotonin synthesis by two 5-HT1A receptor antagonists. 965 62

S 16924 showed a pattern of interaction at multiple (>20) native, rodent and cloned, human (h) monoaminergic receptors similar to that of clozapine and different to that of haloperidol. Notably, like clozapine, the affinity of S 16924 for hD2 and hD3 receptors was modest, and it showed 5-fold higher affinity for hD4 receptors. At each of these sites, using a [35S]GTPgammaS binding procedure, S 16924, clozapine and haloperidol behaved as antagonists. In distinction to haloperidol, S 16924 shared the marked affinity of clozapine for h5-HT2A and h5-HT2C receptors. However, an important difference to clozapine (and haloperidol) was the high affinity of S 16924 for h5-HT1A receptors. At these sites, using a [35S]GTPgammaS binding model, both S 16924 and clozapine behaved as partial agonists, whereas haloperidol was inactive. In vivo, the agonist properties of S 16924 at 5-HT1A autoreceptors were revealed by its ability to potently inhibit the firing of raphe-localized serotoninergic neurones, an action reversed by the selective 5-HT1A receptor antagonist, WAY 100,635. In contrast, clozapine and haloperidol only weakly inhibited raphe firing, and their actions were resistant to WAY 100,635. Similarly, S 16924 more potently inhibited striatal turnover of 5-HT than either clozapine or haloperidol. Reflecting its modest affinity for D2 (and D3) autoreceptors, S 16924 only weakly blocked the inhibitory influence of the dopaminergic agonist, apomorphine, upon the firing rate of ventrotegmental area-localized dopaminergic neurones. Further, S 16924 only weakly increased striatal, mesolimbic and mesocortical turnover of dopamine (DA). Clozapine was, similarly, weakly active in these models, whereas haloperidol, in line with its higher affinity at D2 (and D3) receptors, was potently active. In the frontal cortex (FCX) of freely moving rats, S 16924 dose-dependently reduced dialysate levels of 5-HT, whereas those of DA and NAD were dose-dependently increased in the same samples. In contrast, although S 16924 also suppressed 5-HT levels in the striatum and nucleus accumbens, DA levels therein were unaffected. Clozapine mimicked this selective increase in DA levels in the FCX as compared to striatum and accumbens. In contrast, haloperidol modestly increased DA levels in the FCX, striatum and accumbens to the same extent. In distinction to S 16924, clozapine and haloperidol exerted little influence upon 5-HT levels. Finally, the influence of S 16924 upon FCX levels of 5-HT, DA (and NAD) was attenuated by WAY 100,635. In conclusion, S 16924 possesses a profile of interaction at multiple monoaminergic receptors comparable to that of clozapine and distinct to that of haloperidol. In addition, S 16924 is a potent, partial agonist at 5-HT1A receptors. Correspondingly, acute administration of S 16924 decreases cerebral serotoninergic transmission and selectively reinforces frontocortical as compared to subcortical dopaminergic transmission. In line with these actions, S 16924 shows a distinctive profile of activity in functional (behavioral) models of potential antipsychotic activity (companion paper).
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PMID:S 16924 ((R)-2-[1-[2-(2,3-dihydro-benzo[1,4] dioxin-5-Yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), a novel, potential antipsychotic with marked serotonin (5-HT)1A agonist properties: I. Receptorial and neurochemical profile in comparison with clozapine and haloperidol. 973 98

1. Ejaculatory problems and anorgasmia are well-known side-effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT1A and 5-HT1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes. 2. The 5-HT1A receptor agonist 8-OH-DPAT (0.25-4.00 micromol kg(-1) s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5-HT1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 -carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 micromol kg(-1) s.c.). NAD-299 by itself (0.75-3.00 micromol kg(-1) s.c.) did not affect the male rat ejaculatory behaviour. 3. The 5-HT1B receptor agonist anpirtoline (0.25-4.00 micromol kg(-1) s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5-HT1B receptor antagonist isamoltane (16 micromol kg(-1) s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorphol ino methansulphonate (NAS-181) (16 micromol kg(-1) s.c.). Isamoltane (1.0-16.0 micromol kg(-1) s.c.) and NAD-181 (1.0-16.0 micromol kg(-1) s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non-selective 5-HT1 receptor antagonist (-)-pindolol (8 micromol kg(-1) s.c.), did not antagonize the inhibition produced by anpirtoline. 4. The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT1A and 5-HT1B receptors, respectively, suggesting that the SSRI-induced inhibition of male ejaculatory dysfunction is due to 5-HT1B receptor stimulation.
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PMID:Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. 988 65

Single-unit recording studies were undertaken in chloral hydrate-anesthetized rats to compare the effects on dorsal raphe cell firing of several putative 5-hydroxytryptamine (HT)1A receptor antagonists, including WAY 100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide), p-MPPI (4-(2-methoxyphenyl)1-[2'-[N-(2"-pyridinyl)-p-iodobenzamido]ethyl] pip erazine), and two newly described 5-HT1A receptor antagonists, NDL-249 [(R)-3-(N-propylamino)-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide] and NAD-299 [(R)-3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-1-benzopyran-5-carboxamide]. Consistent with a 5-HT1A receptor antagonist profile, pretreatment with an approximately equimolar (0.02-0.03 micromol/kg) i.v. dose of each compound caused a significant rightward shift in the dose-response curve for 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin]. Antagonist potency was clearly highest for NAD-299 and WAY 100635, which caused shifts roughly 3 times greater than those for either p-MPPI or NDL-249 (ED50 for 8-OH-DPAT, 1.3 +/- 0.3 microg/kg; after NAD-299, 18.2 +/- 1.0 microg/kg; after WAY 100635, 16.9 +/- 2.9 microg/kg; after NDL-249, 6.0 +/- 1.2 microg/kg; after p-MPPI, 4.7 +/- 1.1 microg/kg). In separate studies, each of the antagonists was administered alone in increasing cumulative doses to evaluate whether they possessed intrinsic agonist activity in this system. At doses below 0.01 micromol/kg, none of the drugs altered firing by more than +/-20% basal rates. At higher doses (>0.1 micromol/kg), WAY 100635, NDL-249, and NAD-299 caused a dose-dependent suppression of dorsal raphe cell firing (ED50 = 0.6 +/- 0.2, 0.7 +/- 0.3, and 0. 9 +/- 0.4 micromol/kg, respectively). However, the ED50 values for inhibition by these drugs were roughly 30 times higher than the doses that antagonized effects of 8-OH-DPAT. Moreover, the inhibition by all three antagonists (but not 8-OH-DPAT) was readily reversed by d-amphetamine (3.2 mg/kg i.v.), a releaser of norepinephrine, suggesting that these effects were likely due to alpha adrenergic receptor blockade rather than to 5-HT1A receptor agonism. Thus, it was concluded that WAY 100635, NAD-299, NDL-249, and p-MPPI all fulfill criteria as 5-HT1A receptor antagonists lacking intrinsic efficacy in the dorsal raphe system. The newly described compound NAD-299 exhibits antagonist potency comparable to that of WAY 100635 in this electrophysiological assay.
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PMID:Electrophysiological comparison of 5-Hydroxytryptamine1A receptor antagonists on dorsal raphe cell firing. 991 94

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

The selective 5-HT1A receptor antagonist NAD-299 ([R]-3-N,N-dicyclobutylamino-8-fluoro-3,4- dihydro-2H-1-benzopyran-5-carboxamide) was labeled with the positron-emitting radionuclide carbon-11. The radioligand was synthesized from NAD-195 ([R]-3-N,N-dicyclobutylamino-8-fluoro-5-trifluoromethylsulfonyl oxy-3,4- dihydro-2H-1-benzopyran) in two radiochemical steps. A palladium-catalyzed reaction of NAD-195 and [11C]cyanide was followed by hydrolysis of the carbon-11-labeled nitrile intermediate with basic hydrogen peroxide. The total radiochemical yield, based on [11C]CO2 and corrected for decay, was 20-40%. The specific radioactivity was 24 GBq/mumol (900 Ci/mmol) at end of synthesis, with a radiochemical purity better than 99% and a total synthesis time of 40-45 min. Autoradiographic examination of [11C]NAD-299 binding in human brain postmortem demonstrated high binding in hippocampus, raphe nuclei, and neocortex. The binding in the hippocampus was higher than in the neocortex. Within the hippocampus, the densest binding was observed in the CA1 region. [11C]NAD-299 binding was inhibited by addition of the 5-HT1A receptor ligands WAY-100635, pindolol, (+/-)-8-OH-DPAT, 5-HT, and buspirone, leaving a low background of nonspecific binding. The results indicate that [11C]NAD-299 binds specifically to 5-HT1A receptors in the human brain in vitro and is a potential radioligand for positron emission tomography (PET) examination of 5-HT1A receptors in vivo.
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PMID:Radiosynthesis and autoradiographic evaluation of [11C]NAD-299, a radioligand for visualization of the 5-HT1A receptor. 1010 Feb 14

The 5-HT1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-11C] WAY-100635 (WAY), [carbonyl-11C]desmethyl-WAY-100635 (DWAY), p-[18F]MPPF and [11C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET.
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PMID:Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system. 1120 45

Factors influencing the disappearance of radioactivity from mouse brain after injections of tracer doses of the very selective receptor antagonists [3H]raclopride and [3H]robalzotan (NAD-299) which bind with high affinity to dopamine-D2 and 5-hydroxytryptamine1A receptors, respectively, were studied. For both ligands the amount of radioactivity in cerebellum was taken as non-specific binding and subtracted from the amount of radioactivity found in the brain regions studied. The disappearance of the radioactivity in naive mice followed apparent first-order reactions with T1/2=16.8+/-1.4 min for [3H]raclopride in striatum and T1/2=22+/-2 min and 17+/-2 min for [3H]robalzotan in hippocampus and frontal cortex, respectively. Pretreatment of mice with 1 mg/kg s.c. reserpine 20 h before the experiment strongly prolonged the dissociation phase for the two ligands. Injection of the dopamine-D2 receptor antagonist etioclopride 1 h after [3H]raclopride in the reserpinized mice rapidly reduced the radioactivity in striatum to the same level as in cerebellum. Similarly, the 5-HT1A receptor antagonist WAY-100,635 injected 1 h or 4 h after [3H]robalzotan rapidly reduced the radioactivity in hippocampus and frontal cortex to the cerebellum level showing that the intact drugs were still bound to the receptors. In reserpinized mice kept at 30 degrees C 1 h before and during the experiment, which normalised the body temperature, the disappearance of radioactivity was more like that in untreated animals but was still significantly higher than in the control animals. Mice treated with anaesthetic agents, e.g. gamma-butyrolactone (GBL), pentobarbital sodium and chloral hydrate, also strongly prolonged the rate of disappearance of [3H]raclopride and [3H]robalzotan from the receptor-rich brain regions. The pronounced effect of hypothermia on the dissociation of these 3H ligands from their receptors is probably caused by a general decrease in brain nervous activity. However, the decreased rate of dissociation evoked by reserpine, GBL, baclofen and prazosin after normalisation of the body temperature may be due to specific actions of these compounds causing decrease in dopaminergic and serotoninergic nerve activity which results in reduced synaptic concentration of the transmitter amines. In accordance with this view, increased synaptic 5-HT evoked by the 5-HT releasing agent p-chloroamphetamine enhanced the disappearance of [3H]robalzotan from hippocampus and frontal cortex.
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PMID:Hypothermia reduces the rate of dissociation of specific ligands from dopamine-D2 and 5-hydroxytryptamine1A receptors in the mouse brain in vivo. 1169 32


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