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)

Pigeon cerebrospinal fluid was assayed for 5-HT (5-hydroxytryptamine) and catecholamine metabolites after systemic drug injection. The 5-HT1-like receptor agonists 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1H indole (RU 24969), 1-(m-trifluoromethylphenyl)piperazine (TFMPP), and 1-(3-chlorphenyl)piperazine (mCPP) decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) without altering other metabolites. 5-HIAA decreases occurred at doses of 8-OH-DPAT and RU 24969 that have anti-conflict effects in pigeons, whereas TFMPP and mCPP decreased 5-HIAA only at behaviorally disruptive doses. The novel compound 1-(2-methoxyphenyl)-1-(4-(2-phthalimido)butyl)piperazine (NAN-190), a putative 5-HT1A receptor antagonist, did not affect 5-HIAA, but attenuated the decreases produced by the agonists. NAN-190 and the alpha 1-adrenoceptor antagonist prazosin increased levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol and had additive effects when co-administered. The rank order of potency in inhibiting [3H]8-OH-DPAT binding in pigeon cerebrum was 8-OH-DPAT = RU 24969 > NAN-190 >> mCPP > TFMPP. The results support suggestions that decreased 5-HT neurotransmission underlies the anxiolytic-like effects of 5-HT1A receptor agonists in pigeons.
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PMID:Neurochemical effects of 5-HT1 receptor ligands in pigeons. 128 73

The synthesis and the 5-HT1A and 5-HT2 receptor affinity of 2-substituted 1-[3-(4-aryl-1-piperazinyl)propyl]-imidazoles (1-8) has been described. It has been shown that both the N-3 imidazole atom and the N-1 piperazine one should be considered as possible protonation centers under physiological conditions. It has been found that the folded conformations of 1-8 exist predominantly in solution. Moreover, three different modes of interaction of the analyzed compounds with 5-HT1A and 5-HT2 receptor sites have been proposed.
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PMID:Structure-activity relationship studies of CNS agents. Part VII. The effect of the imidazole fragment in 2-substituted 1-[3-(4-aryl-1-piperazinyl)propyl]imidazoles on their interaction modes with 5-HT1A and 5-HT2 receptors. 129 15

The interaction at 5-hydroxytryptamine (5-HT) receptors of the novel naphtylpiperazine, S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine), was compared to that of the 5-HT1A ligands, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), WY 50,324 [N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) )- decane-1-carboxamide], (+)-flesinoxan, buspirone and BMY 7378 [(8-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-8-azaspirol[-4-]-decane-7,9-dione 2HCl]. S 14671 showed a very high affinity for 5-HT1A sites (pKi, 9.3) as compared to the reference ligands (pKi values, 9.2, 8.7, 8.7, 7.9 and 8.7, respectively). S 14671 bound in an apparently competitive manner and, in distinction to the reference compounds, possessed a Hill Coefficient (1.4) significantly superior to 1. Although showing low affinity at 5-HT1B and 5-HT3 sites, S 14671 displayed significant affinity at both 5-HT1C and 5-HT2 sites; pKi, 7.8 in each case. Furthermore, S 14671 acted as an antagonist of 5-HT-stimulated phosphoinositide turnover in rat choroid plexus (5-HT1C) and cortex (5-HT2). In vivo, upon s.c. administration, S 14671 acted as a high efficacy agonist in models of 5-HT1A receptor-mediated activity: induction of flat-body posture, spontaneous tail-flicks, hypothermia and corticosterone secretion and inhibition of morphine-induced antinociception. In every test, S 14671 was the most potent compound: it was active at doses as low as 5 micrograms/kg s.c. Relative potency across all tests was S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than (+)-flesinoxan greater than buspirone with BMY 7378 too weak for comparison to be meaningful. The action of S 14671 in 5-HT1A tests was blocked by BMY 7378 and the 5-HT1A antagonist, (-)-alprenolol, but unaffected by the 5-HT1C/2 antagonist, ritanserin, and the 5-HT3 antagonist, ondansetron. Activation of postsynaptic 5-HT1A receptors was confirmed in 5,7-dihydroxytryptamine-lesioned rats, in which the potency of S 14671 to elicit spontaneous tail-flicks was potentiated. Activation of presynaptic receptors was demonstrated by inhibition of the electrical activity of the dorsal raphe nucleus with the following order of relative potency: S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than BMY 7378 greater than buspirone. Spiperone, which acts as a pure 5-HT1A antagonist at raphe 5-HT1A receptors, blocked the action of S 14671. In conclusion, S 14671 is a structurally novel ligand manifesting high efficacy and exceptional potency at both pre- and postsynaptic 5-HT1A receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:S 14671: a naphtylpiperazine 5-hydroxytryptamine1A agonist of exceptional potency and high efficacy possessing antagonist activity at 5-hydroxytryptamine1C/2 receptors. 132 50

1. Vasoactive intestinal polypeptide (VIP) stimulated adenosine 3':5'-cyclic monophosphate (cyclic AMP) production by cultured GH4ZD10 cells with an EC50 value of about 7 nM. The extracellularly recovered cyclic AMP predominated, and was reduced by co-incubation with 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT), whereas dopamine (0.1-30 microM) did not reduce VIP-stimulated cyclic AMP production. 2. The responses to 5-HT and 8-OH-DPAT were blocked by (-)-alprenolol and NAN 190. The antagonism by (-)-alprenolol was competitive in nature with a pA2 value of 7.0. 3. The responsiveness of the cells to 5-HT agonists was highly dependent upon the culturing conditions used. Thus, 8-OH-DPAT inhibition of VIP (30 nM)-stimulated cyclic AMP production decreased with increasing passage number of the cells. Reduction of the zinc concentration used to promote expression of the 5-HT1A receptor gene produced a greater sensitivity of the cells to 5-HT agonists. 4. Under such conditions, the following efficacies (5-HT = 100) were found: lisuride 106, (+)-lysergic-acid diethylamide 100, 5-methoxy-N,N-dimethyltryptamine 98, RU 24949 98, 5-carboxamidotryptamine 97, (+/-)-8-OH-DPAT 90, (+)-8-OH-DPAT 87, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine 86, flesinoxan 79/88, (-)-8-OH-DPAT 62, buspirone 43/50, ipsapirone 46. Spiroxatrine and spiperone had a low intrinsic activity, but reduced the response to 5-HT. These efficacies are similar to those reported in the literature for post-synaptically localized 5-HT1A receptors in the rat hippocampus. Thus, the GH4ZD10 cells serve as a useful in vitro model system for these receptors.
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PMID:GH4ZD10 cells expressing rat 5-HT1A receptors coupled to adenylyl cyclase are a model for the postsynaptic receptors in the rat hippocampus. 133 Jan 57

Bovine pulmonary artery smooth muscle (SM) cells express a novel 5-hydroxytryptamine (5-HT) (5-HT4-like) receptor coupled to cAMP accumulation. cAMP radioimmunoassay established the agonist and antagonist profiles of this receptor. 5-HT (EC50 = 91 +/- 33 nM) and 5-methoxytryptamine were equipotent at the SM cell 5-HT receptor and both were more potent than 5-carboxamidotryptamine. Other tryptamine derivatives were less potent but remained full agonists. These findings are consistent with previous reports regarding 5-HT4 and 5-HT4-like receptors in the central nervous system. The most potent antagonists were the antidepressant compounds nortriptyline (IC50 = 177 +/- 153 nM) and zimelidine (IC50 = 202 +/- 101 nM). The 5-HT3 and 5-HT4 antagonist 3-tropanyl-indole-3-carboxylate (ICS 205-930) was also a competitive antagonist at this 5-HT4-like receptor (pA2 = 6.3). Antagonist affinities differed slightly at the SM cell receptor, compared with other 5-HT4 and 5-HT4-like receptors in the central nervous system. Nonetheless, the SM cell 5-HT4-like receptor displayed the same differential antagonist potencies as reported for these other receptors (ICS 205-930 > MDL 72222 and mianserin > ketanserin). 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was the most potent agonist for this 5-HT4-like receptor (EC50 = 6.4 +/- 3.4 nM). 8-OH-DPAT-induced cAMP accumulation could be blocked by ICS 205-930 but not by the 5-HT1A antagonist 1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine hydrobromide, distinguishing the SM cell 5-HT receptor from 5-HT1A receptors. The mechanism of 5-HT-stimulated cAMP production was also investigated. First, GTP augmented basal and 5-HT-stimulated cAMP accumulation. Second, antisera to the carboxyl terminus of the alpha subunit of Gs, attenuated 5-HT-mediated adenylate cyclase activation. This established that 5-HT-stimulated cAMP accumulation in SM cells required GS. These findings suggest that SM cells express a novel 5-HT4-like receptor positively coupled to adenylate cyclase. An unexpected finding was that 8-OH-DPAT is a potent partial agonist. These studies suggest that there may be heterogeneity among 5-HT4-like receptors.
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PMID:8-hydroxy-2-(di-n-propylamino)tetralin-responsive 5-hydroxytryptamine4-like receptor expressed in bovine pulmonary artery smooth muscle cells. 133 64

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.
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PMID:Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine. 133 84

The effects of a range of 5-HT receptor antagonists were examined in an animal model of anxiety--the social interaction test. Six antagonists with high affinity for 5-HT1C receptors; mianserin, (+) mianserin, 1-naphthyl piperazine, ICI 169 369, pizotifen and LY 53857 all increased the time spent in active social interaction by pairs of weight-matched rats under high light unfamiliar conditions. As locomotion was only increased by 1-NP and then only at high doses, the effect of the drugs is consistent with anxiolysis. These properties were shared by the benzodiazepine anxiolytic chlordiazepoxide but not by the specific 5-HT2 antagonists ketanserin and altanserin, nor by the 5-HT1A and 5-HT1B antagonists cyanopindolol and pindolol. Similarly, neither the adrenergic alpha 2 antagonist idazoxan, the alpha 2 antagonist and putative 5-HT1D partial agonist yohimbine nor the H1 antagonist mepyramine had any significant effect. Since (+)mianserin, LY 53857 and ICI 169 369 at least have low affinity for 5-HT3 receptors these receptors are also unlikely to be involved. The results therefore imply that the observed anxiolytic effects of the drugs are likely to be mediated by 5-HT1C receptor blockade.
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PMID:5-HT1C receptor antagonists have anxiolytic-like actions in the rat social interaction model. 135 56

At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently. Aryl-piperazine derivatives work as 5-HT1A receptor partial agonists and are known as serotonin normalizers. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective clisadvantages.
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PMID:The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives). 135 1

Administration of various doses of clonidine increased plasma growth hormone levels. Pretreatment with the alpha 2 adrenergic antagonists, yohimbine and 1-(2-pyrimidyl)piperazine, completely blocked clonidine's effect on growth hormone levels. Pretreatment with the 5-hydroxytryptamine3 (5-HT3) receptor antagonist, MDL-72222, the 5-HT1A/5-HT2 antagonist, spiperone, and the mixed beta adrenergic/5-HT1B antagonists, l-propranolol and CGP361A, did not attenuate clonidine-induced increases in growth hormone levels. In contrast, pretreatment with the non-selective 5-HT1/2 antagonist, metergoline, and the 5-HT1C/5-HT2-selective antagonist, mesulergine, reduced clonidine-induced increases in growth hormone levels 81 to 87% without affecting clonidine-induced decreases in locomotor activity. Two other 5-HT1C/5-HT2 antagonists, ritanserin and mianserin, also attenuated (47%) clonidine-induced increases in growth hormone levels. Pretreatment with the noradrenergic neurotoxin, DSP4, did not block clonidine's effect on growth hormone levels. Clonidine administration decreased locomotor activity in both the Fawn-Hooded and the Wistar rat strains to the same extent. On the other hand, clonidine administration failed to increase growth hormone levels in the Fawn-Hooded rat strain. These findings suggest that clonidine stimulates growth hormone secretion by activation of alpha 2 adrenergic heteroreceptors present on 5-HT nerve terminals which, in turn, enhance 5-HT activity via stimulation of postsynaptic 5-HT1C receptors to promote growth hormone releasing factor. Furthermore, either 5-HT1C receptors or alpha 2 adrenergic heteroreceptors or both are functionally sub-sensitive in the Fawn-Hooded rat strain relative to the Wistar rat strain.
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PMID:Functional subsensitivity of 5-hydroxytryptamine1C or alpha 2 adrenergic heteroreceptors mediating clonidine-induced growth hormone release in the Fawn-Hooded rat strain relative to the Wistar rat strain. 135 49

It has been established in experiments on spinal ganglia neurons of rats that 1-pyrimidinyl-piperazine derivatives show the properties of partial agonists of 5-HT1A-receptors. Some of them were discovered to be capable of blocking D2-dopamine receptors. Comparison of neuronal and behavioral activity of the substances tested has demonstrated that their anxiolytic activity detectable under the conditions of the conflict situation method significantly correlates with 5-HT1A-mimetic and anti-dopamine activity. The latter one correlates well with the influence of the substances tested on the time of immobilization in the forced swimming test.
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PMID:[The serotonin- and dopaminergic mechanisms in the action of 1-pyrimidinyl piperazine derivatives]. 136 Aug 56

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