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)

Male Wistar rats were trained to discriminate the interoceptive effects of 5-methoxy-N,N-dimethyltryptamine (5-OMe-DMT; 1.25 mg/kg, IP) from saline in a two-lever operant chamber. Following discrimination learning, the following drugs (with ED50 dose in mg/kg IP) dose-dependently generalized: lysergic acid diethylamide (LSD, 0.04), 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.11), 6-methoxy-4-(dipropyl-amino)-1,3,4,5-tetrahydrobenz(c,d)indole hydrochloride (BAY R 1531, 0.15), 5-OMe-DMT itself (0.63), ipsapirone (TVX Q 7821, 2.7), and buspirone (3.8). The potencies of these drugs in generalization tests were best correlated with their binding affinities for the 5-HT1A serotonin receptor subtype (as measured by displacement of 3H-ipsapirone in the hippocampus). Drugs not, or only partially generalizing included quipazine, bufotenin, m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-3(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole succinate (RU 24969), citalopram, clomipramine, 1,4-dihydro-2,6-dimethyl-3-nitro-4(2-trifluoromethylphenyl)-pyridine-5- carboxylate (BAY K 8644), the buspirone metabolite 1-pyrimidinyl-piperazine (1-PP), methysergide, metergoline, and metitepine. Of the last three compounds with antagonistic activity at 5-HT receptors, as well as ketanserin, pizotifen, and ritanserin, only metitepine and pindolol could fully block the 5-OMe-DMT stimulus. Pizotifen blocked the generalization of quipazine fully, that of 5-OMe-DMT only partially, and that of ipsapirone not at all. These data indicate that the 5-HT1A receptor subtype is strongly involved in the transduction of the interoceptive discriminative stimuli induced by 5-OMe-DMT, with 5-HT2 agonism also playing a possible role.
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PMID:Serotonin receptor subtype mediation of the interoceptive discriminative stimuli induced by 5-methoxy-N,N-dimethyltryptamine. 312 48

We have synthesized 8-methoxy-2-(N-2'-chloropropyl, N-propyl) aminotetralin (8-methoxy-2'-chloro-PAT), an alkylating agent derived from the potent 5-HT agonist, 8-hydroxy-2-(N,N-dipropyl)-aminotetralin (PAT). As expected for an irreversible ligand, the blockade of 3H-PAT or 3H-5-HT binding to post-synaptic 5-HT1 (A and B) sites in rat hippocampal membranes pretreated with 8-methoxy-2'-chloro-PAT could not be prevented by extensive washing of membranes. Prior occupancy of 5-HT1 sites by 5-HT or PAT prevented any subsequent irreversible blockade by the alkylating agent. Similar irreversible blockade by 8-methoxy-2'-chloro-PAT was found on 3H-PAT binding to striatal membranes suggesting that presynaptic 5-HT binding sites (see Gozlan et al., Nature, Lond. 305, 140, 1983) were sensitive also to the alkylating agent. In contrast, the modifying agent N-ethylmaleimide (NEM) reduced markedly 3H-PAT binding to postsynaptic hippocampal 5-HT1 sites, but did not alter 3H-PAT binding to striatal presynaptic 5-HT sites. Although 8-methoxy-2'-chloro-PAT bound irreversibly to different classes of 5-HT binding sites (5-HT1A, 5-HT1B, presynaptic sites), it can be considered a selective alkylating agent, since it exerted no action on 3H-spiperone binding to 5-HT2 sites, 3H-muscimol binding to GABA sites, or 3H-flunitrazepam binding to benzodiazepine sites.
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PMID:Irreversible blockade of central 5-HT binding sites by 8-methoxy-2'-chloro-PAT. 315 2

The distribution of the binding sites of a new, potent agonist of serotonin (5-HT), 8-OH-N,N-dipropyl-2-aminotetralin (PAT), was studied in the rat brain with the quantitative autoradiographic technique utilizing tritium-sensitive LKB film. The localization of [3H]PAT binding sites was very similar to that of [3H]5-HT binding sites, except in some discrete regions (choroid plexus, striatum, area preoptica lateralis, subiculum, and substantia nigra), which exhibited very low levels of labeling with [3H]PAT and high levels with [3H]5-HT. These results indicate that 5-HT1 receptors are heterogeneous, and that [3H]PAT recognizes only a 5-HT1 subclass (called 5-HT1A).
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PMID:Autoradiographic evidence for the heterogeneity of 5-HT1 sites in the rat brain. 623 Jan 36

Release of substance P-like immunoreactivity (SP-LI) from dissociated enteric ganglia and the receptor-mediated prejunctional inhibition of this release were investigated with the use of a perifusion technique. SP-LI release was evoked by elevated extracellular K+ concentration and was inhibited, in a graded manner, by N6-cyclopentyl adenosine (CPA), an adenosine analogue with selectivity for adenosine A1 receptors. Similar inhibition of SP-LI release was obtained with 5-hydroxytryptamine (5-HT); incrementing concentrations, however, yielded a biphasic concentration-response relationship. The selective adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentyl-xanthine abolished the inhibition due to CPA, whereas the inhibitory action of 5-HT was sensitive to the 5-HT1A-selective antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide. Inhibition due to both agonists was insensitive to blockade by tetrodotoxin, suggesting a prejunctional locus for both adenosine and 5-HT1A receptors on the tachykininergic nerve endings. Pretreatment of ganglia with pertussis toxin had no effect on CPA-mediated inhibition of SP-LI release, whereas 5-HT-mediated inhibition was abolished. The findings demonstrate that adenosine and 5-HT receptors on enteric nerve endings are coupled to inhibition of tachykinin release through distinct mechanisms, putatively distinct G proteins.
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PMID:Adenosine and 5-HT inhibit substance P release from nerve endings in myenteric ganglia by distinct mechanisms. 768 28

In order to explore further the structure-activity relationships of serotonergic and dopaminergic ligands, a series of enantiopure 5-, 7-, or 8-triflate (-OTf)-substituted 2-(monopropylamino)-tetralins have been synthesized and evaluated in in vitro binding and in vivo biochemical and behavioral assays in rats. Consequently, the 8-OTf-substituted compound R-(+)-6 was found to be a potent and selective 5-HT1A (5-hydroxytryptamine) receptor agonist inducing a full-blown 5-HT syndrome in normal rats, while the corresponding 5-OTf-substituted compound S-(-)-12 was found to be a preferential dopamine (DA) autoreceptor agonist. A partial 5-HT syndrome was also observed for S-(-)-12, while the corresponding R-(+)-12 was found to be inactive at the DA and 5-HT receptors both in vitro and in vivo. Compounds 6 and 12 were found to be major urinary metabolites following oral administration of their dipropyl analogs (2 and 13, respectively). Thus 6 was proposed to be the metabolite responsible for the full-blown 5-HT syndrome seen after oral (but not subcutaneous) administration of 2. Similarly, 12 was proposed to be the metabolite responsible for the partial 5-HT syndrome seen after oral (but not subcutaneous) administration of 13. The bioavailability of R-(+)-6 (7.6 +/- 1.1%) appeared to be slightly lower than that of 2 (11.2 +/- 5.2%), although the in vitro metabolism of R-(+)-6 appeared to be slower than that of 2. Therefore first-pass metabolism was not thought to be the reason for the lower bioavailability of R-(+)-6, as compared to 2.
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PMID:Synthesis and evaluation of pharmacological and pharmacokinetic properties of monopropyl analogs of 5-, 7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: central dopamine and serotonin receptor activity. 773 Oct 17

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs. N, N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) is a novel compound with high affinity for the sigma receptor (IC50 = 4.16 nM), but low affinity (IC50 > 10,000 nM) for D1, D2, 5-HT1A, 5-HT2 and phencyclidine (PCP) receptors. The head-weaving behavior induced by either (+)SKF10047 or PCP was dose-dependently antagonized by NE-100 with oral ED50 at 0.27 and 0.12 mg/kg, respectively. NE-100 did not affect dopamine agonists-induced stereotyped behavior and/or hyperactivity. NE-100 failed to induce catalepsy in rats. These findings indicate that NE-100 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics.
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PMID:NE-100, a novel sigma receptor ligand: in vivo tests. 790 23

U-67413B (4-hydroxydipropylaminodihydrophenalene) bound with high affinity to both 5-hydroxytryptamine (HT)1A and D2-dopamine (DA) receptor sites. U-67413B depressed 5-HT and DA cell firing rates and depressed synthesis of both neurotransmitters. The drug depressed mouse body temperatures by an amount similar to that for buspirone, gepirone and ipsapirone, but less than that for 8-hydroxy-N,N-dipropyl-2-aminotetralin. In rats, it produced the 5-HT1A behavioral syndrome. In contrast to 5-HT1A agonists having DA antagonist effects, U-67413B mildly depressed rather than stimulated firing rates of noradrenaline (NA) neurons in the locus ceruleus by a non-alpha-2 receptor mechanism. In behavioral tests designed to measure anxiolytic activities, U-67413B was a slightly more effective anxiolytic than standard 5-HT1A anxiolytics (buspirone, gepirone and ipsapirone). The data are consistent with the hypothesis that effects of 5-HT1A agonists on NA neuron activity are mediated through effects on dopaminergic mechanisms, and that effects on NA neurons could modulate anxiolytic activities of 5-HT1A agonists.
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PMID:Pharmacology of a mixed 5-hydroxytryptamine1A/dopamine agonist. 790 53

The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.
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PMID:Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist. 796 8

1. RS-15385-197, a highly potent and selective alpha 2-adrenoceptor antagonist, was examined in a variety of in vitro and in vivo functional tests to assess the selectivity of its interaction with central noradrenergic neurones in the rat. 2. In hypothalamic slices, RS-15385-197 was potent in augmenting K(+)-evoked release of [3H]-noradrenaline, with an EC50 of 9 nM. Idazoxan and yohimbine showed 100 fold less activity. This was due to its antagonist action at presynaptic alpha 2-adrenoceptors, as RS-15385-197 (10 microM), did not directly release [3H]-noradrenaline from cortical slices unlike reserpine (10 microM), and did not inhibit noradrenaline re-uptake into cortical synaptosomes. 3. In vivo, RS-15385-197 (0.5 mg kg-1, p.o.) increased levels of 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the cerebral cortex without modifying levels of 5-hydroxyindoleacetic acid (5-HIAA). This dose, but not a lower dose (0.1 mg kg-1, p.o.) caused beta-adrenoceptor down-regulation in the cortex when administered once daily for 14 days whereas 5-HT2 receptor number was unaltered, indicating a selective effect on noradrenergic transmission. 4. Selective depletion of cortical 5-HT by administration of p-chlorophenylalanine (PCPA; 100 mg kg-1, i.p. for 14 days) or 5,7-dihydroxytryptamine (5,7-DHT; 150 micrograms i.c.v.) prevented the beta-adrenoceptor down-regulation caused by RS-15385-197, indicating that a tonic 5-hydroxytryptaminergic input was required for it to elicit beta-adrenoceptor down-regulation. It was not possible to prevent the loss of activity of RS-15385-197 in these 5-HT-depleted animals by co-administration with the 5-HT1A partial agonist, 8-hydroxy-n-dipropyl aminotetralin (8-OH-DPAT, 0.3 mg kg-1, i.p. twice daily for final 3 days).5. At a dose (1 mg kg-1, p.o.) which completely prevented the hypoactivity produced by clonidine(0.1 mgkg-1, p.o.), RS-15385-197 did not affect behavioural stereotypy induced by 8-OH-DPAT(0.3 mg kg-1, s.c.). Similarly, following chronic dosing with the racemate, RS-15385-196 (3 mg kg-1,p.o., once daily for 14 days), there was no effect on the behavioural and hypothermic response to 8-OH-DPAT (0.5 mg kg-1, s.c.). Therefore, RS-1 5385-197 was selective for central alpha2-adrenoceptors over 5-HT1A receptors in in vivo functional tests.6. Thus, RS-15385-197 was highly selective in interacting with central noradrenergic neurones in the rat in vitro and in vivo. It is therefore currently the agent of choice for investigations of the role of alpha 2-adrenoceptors in the CNS.
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PMID:Modulation of central noradrenergic function by RS-15385-197. 809 21

The purpose of the present study was to investigate the effect of microinjection of serotonin (5-HT) and selected 5-HT receptor subtype agonists and antagonists into the caudal nucleus raphe obscurus on gastrointestinal motor activity in urethane-chloralose anesthetized rats. Serotonin (0.6-18.0 nmol) dose-dependently increased intragastric pressure, and this effect was abolished by peripherally administered atropine (0.5-1.0 mg/kg, i.v.). Microinjection of a 5-HT1A receptor agonist, 8-hydroxy-N,N-dipropyl-2-amino-tetralin hydrobromide (0.06-12.0 nmol), a 5-HT1C/2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (4.5 and 18.0 nmol), as well as a 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide hydrochloride (0.6-18.0 nmol), also resulted in increases in intragastric pressure. The gastric excitatory effect of 5-HT (6.0 nmol) was markedly reduced by prior microinjection of a 5-HT1/2 receptor antagonist, methiothepin (200 nmol), into the same site, as well as by i.v. administration of a 5-HT2/1C antagonist, ketanserin (2.5 mg/kg). The effect of 5-HT (6.0 nmol) on intragastric pressure was completely blocked by i.v. administration of a mixture of the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazinehydrobromide++ + (3.5 mg/kg), ketanserin (2.5 mg/kg) and the 5-HT3 receptor antagonist 3-tropanyl-3,5-dichlorobenzoate (2.5 mg/kg). These results indicate that 5-HT activates gastric motor function in the caudal nucleus raphe obscurus via a vagally mediated pathway and that the activation of multiple 5-HT receptor subtypes is required for the gastric excitatory effect of 5-HT.
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PMID:Serotonin microinjected into the nucleus raphe obscurus increases intragastric pressure in the rat via a vagally mediated pathway. 809 47


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