Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzene-acetamide methane sulfonate (U-50,488H), a kappa-opiate agonist-induced tolerance and abstinence on 5-HT1A receptors was determined in regions of the brain and spinal cord of the rat. The administration of U-50,488H (25 mg/kg, i.p., twice daily) to male Sprague-Dawley rats for 4 days resulted in the development of almost complete tolerance to its analgesic and hypothermic effects. On day 5, the animals were divided into tolerant and abstinent groups and sacrificed. The brain and spinal cord were excised from all groups of rats and the brain was dissected into 6 regions, namely, amygdala, hypothalamus, striatum, midbrain, pons+medulla and cortex. The 5-HT1A receptors were characterized by using [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]DPAT) as the ligand. The binding constants (Bmax and Kd values) of [3H]DPAT in regions of the brain and spinal cord of rats tolerant to U-50,488H and vehicle did not differ. However, the Bmax value of [3H]DPAT in the hypothalamus of U-50,488H-abstinent rats was decreased but the Kd value did not change. In the other regions of the brain and spinal cord of U-50,488H-abstinent rats, the Bmax and Kd values of [3H]DPAT were unaffected. Subcutaneous administration of DPAT produced hypothermic response in vehicle- and U-50,488H-treated rats. The intensity of this effect was more marked in U-50,488H-abstinent group. It is concluded that 5-HT1A receptors are down-regulated in the hypothalamus of U-50,488H-abstinent rats but the hypothermic response to 5-HT1A agonist is intensified.
 ...
PMID:Abstinence from U-50,488H, a kappa-opiate receptor agonist, decreases the binding of [3H]DPAT to 5-HT1A receptors in the hypothalamus of the rat. 147 Mar

This study examined the effects of structurally diverse 5-hydroxytryptamine (HT)1A partial agonists upon opioid-induced antinociception against noxious heat and pressure stimuli in rats and mice. The pyrimidinylpiperazines, buspirone, ipsapirone and gepirone, the halogenated phenylpiperazine, LY 165, 163 [1-(2-(4-aminophenyl)ethyl-4-(3-trifluoromethylphenyl)-piperazine], the heterobicylic arylpiperazine, (+/-)-flexinoxan, and the benzodiaxane, MDL 728328-[(4-(1,4-benzodioxon-2-ylmethylamino)butyl-8-azasp iro-(4,5)-decane-7,9-dione], exerted little or no effect upon basal latencies. In both mice and rats, each dose-dependently attenuated the antinociceptive action of the mu-opioid, morphine, against heat and pressure. In their presence, the morphine dose-response curve was shifted in parallel to the right with no loss of maximal effect. In mice, Schild analysis of the action of ipsapirone and gepirone yielded slopes of close to -1. In contrast to the partial agonists, the buspirone metabolite, 1-pyrimidinylpiperazine, which lacks 5-HT1A affinity, and the putative 5-HT1A antagonists, methiothepin, spiperone, BMY 7378 [(8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol [4]-decane-7,9-dione) 2HCl] and alprenolol, did not reduce the action of morphine. In rats, the antagonistic effect of buspirone, gepirone and ipsapirone could be blocked by BMY 7378. The 5-HT1A partial agonists also antagonized the antinociception-induced by the mu-opioid, sufentanil, but were virtually inactive against the selective kappa-opioid agonists, U69,593 (5 alpha,7 alpha,8 beta-(+)-N-methyl-N-[7-(l-pyrrolidinyl)-1-oxaspirol-(4,5)-dec-8-yl ] benzene-acetamide) and U50,488H (trans-(dl)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]-benzenacetamide methane sulfonate hydrate.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:5-hydroxytryptamine (HT)1A receptors and the tail-flick response. III. Structurally diverse 5-HT1A partial agonists attenuate mu- but not kappa-opioid antinociception in mice and rats. 167 81

A structure-activity analysis was used to identify selective 5-HT1A versus 5-HT1D receptor agents. An analysis of published data identified 13 drugs which display nanomolar affinity for the 5-HT1A receptor and that have been analyzed at 5-HT1D receptor binding sites. Four agents display greater than or equal to 100-fold selectivity for the 5-HT1A receptor. Two structural features were identified which hypothetically result in selectivity for 5-HT1A versus 5-HT1D binding sites. The linkage of an indole ring to a basic nitrogen atom via the 4 position on the indole ring or the absence of an indole ring are two features which lower the affinity for the 5-HT1D receptor, but do not necessarily lower the affinity for the 5-HT1A receptor. A series of 7 agents (5 indoles, 2 quinolines) was identified which met these hypothetical selectivity criteria. These compounds were then analyzed in radioligand binding studies. These 7 agents display affinities of 1.3-170 nM for the 5-HT1A receptor binding site, and 1,800-13,000 nM for the 5-HT1D receptor binding site. All 7 agents display greater than or equal to 47-fold selectivity for the 5-HT1A versus 5-HT1D site and 4 of the agents are greater than 100-fold selective. Compound No. 1 (N,N'-bis[3-(4-indolyloxy)-2-hydroxypropyl]-(Z)-1,8-diamino-p-meth ane) and compound No. 2 (N8-[3-(4-indolyloxy)-2-hydroxypropyl]-N1-(propioloyl)-(Z)-1 ,8-diamino-p-methane) are the most selective agents yet described for 5-HT1A versus 5-HT1D receptor binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Structural determinants of 5-HT1A versus 5-HT1D receptor binding site selectivity. 206 May 96

The 5-hydroxytryptamine (5-HT) receptor mediating endothelium-dependent relaxation of pig coronary arteries was characterized using a variety of 5-HT receptor agonists and antagonists. Unrubbed (with endothelium preserved) rings precontracted by prostaglandin F2 alpha in the presence of ketanserin relaxed in an endothelium-dependent manner to 5-HT, 5-carboxamidotryptamine and 5-methoxytryptamine with about equal potency and efficacy. By comparison, bufotenine, 3-(dimethylamino)ethyl-N-methyl-1H-indole-5-methane sulfonamide, (-)-alpha-methyl-5-HT,N,N-dipropyl-5-carboxamidotryptamine and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole were half-efficient and other drugs [in particular the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin] were inactive as agonists up to 0.1 mM. The effect of 5-carboxamidotryptamine was antagonized in an apparently competitive manner by 15 drugs. Among the most potent antagonists (mean pKB value) were the nonselective 5-HT receptor antagonists, methiothepin (7.30) and metergoline (6.86), the 5-HT1A/5-HT1D receptor ligand, 1-[2-(4-amino-phenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine (7.02), the 5-HT1A/5-HT1B/5-HT1D receptor ligand, 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2,-a]quinoxaline 1 (6.73) and yohimbine (6.37). Selective ligands for 5-HT1A receptors were either inactive [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide] or poorly active (spiperone, 4.44). Beta-adrenoceptor antagonists with affinity for 5-HT1A and 5-HT1B receptors weakly antagonized the effect of 5-carboxamidotryptamine (pKB values less than or equal to 5.32), as did the 5-HT1c/5-HT2 receptor antagonist, mesulergine (5.30) and the yohimbine isomer, corynanthine (4.85). Methysergide was clearly a noncompetitive antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:5-Hydroxytryptamine (5-HT)-induced endothelium-dependent relaxation of pig coronary arteries is mediated by 5-HT receptors similar to the 5-HT1D receptor subtype. 213 76

The ability of sumatriptan (GR 43175; 3-[2-dimethylamino]ethyl-N-methyl-1H-indole-5 methane sulphonamide) to interact with 13 neurotransmitter receptor sites was determined using radioligand binding techniques. Sumatriptan displayed the highest affinity for 5-HT1D (Ki = 17 nM) and 5-HT1B (Ki = 27 nM) binding sites and was slightly less potent at 5-HT1A binding sites (Ki = 100 nM). By contrast, sumatriptan was essentially inactive (Ki greater than 10,000 nM) at each of the 10 other binding sites analyzed. These data indicate that sumatriptan interacts selectively with 5-HT1B and 5-HT1D sites and suggest that these interactions may be the basis of its apparent efficacy in the acute treatment of migraine.
 ...
PMID:Sumatriptan (GR 43175) interacts selectively with 5-HT1B and 5-HT1D binding sites. 254 59

GR 43175 (3-[2-dimethylamino]ethyl-N-methyl-1 H-indole-5 methane sulphonamide) is a novel 5-HT1-like receptor-selective agonist which was reported to be active in the treatment of migraine attacks. The effects of the compound were investigated in radioligand binding studies and in functional models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphate production in pig choroid plexus). GR 43175 displayed the following order of affinity for 5-HT recognition sites (pKD values, -log mol/l, in parentheses): 5-HT1D (7.54) greater than 5-HT1B (6.35) greater than 5-HT1A (6.13) much greater than 5-HT1C (4.13) greater than 5-HT2 (3.67). The same order of potency was observed at functional 5-HT1 receptors, at which GR 43175 acted as a full agonist, with the exception of the 5-HT1C receptor, where the compound was a weak antagonist (pEC50 or pKB values, -log mol/l, in parentheses): 5-HT1D (6.28) greater than 5-HT1B (6.03) greater than 5-HT1A (5.57) much greater than 5-HT1C (4.25). The present data show that GR 43175 interacts preferentially as an agonist with 5-HT1B and 5-HT1D receptors. Since 5-HT1B receptors have not yet been identified in human brain, it seems possible that it is the 5-HT1D receptor which is relevant to the reported antimigraine effects of this compound.
 ...
PMID:How selective is GR 43175? Interactions with functional 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors. 255 30

The genetically dystonic (dtsz) hamster is an autosomal recessive mutant that shares several features with paroxysmal dystonia, i.e., a subcategory of inherited idiopathic dystonia in humans. Because the serotonin (5-HT) system has been suggested to be involved in dystonia, we examined the functional responsiveness of the 5-HT system in dystonic hamsters by administering various 5-HT agonists and antagonists selective for different receptor subtypes and observing the effects on dystonic attacks as well as the behavioural responses associated with drug administration. Paradoxically, marked prodystonic effects (i.e., increased severity and/or decreased latency of dystonic attacks) were seen with both the selective 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and the selective and "silent" 5-HT1A receptor antagonist, N-tert-butyl-3[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropionamide [(+)-WAY-100135], whereas other 5-HT1A receptor antagonists, i.e., methyl 4[4-(4-[1,1,3-trioxo-2H-1,2-benzoiosothiazol-2-yl]butyl)-1- piperazinyl]1-H-indole-2-carboxylate (SDZ 216-525) and N1-bromoacetyl-N8-3'-(4-indolyloxy)-2'-hydroxypropyl-(Z)-1,8- diamino-p-methane (pindobind-5-HT1A) did not alter dystonia to any comparable extent. Because among these 5-HT1A receptor antagonists, (+)-WAY-100135 is the only drug known to be not only silent at postsynaptic but also presynaptic (somatodendritic) 5-HT1A receptors, the marked prodystonic effect of this drug could relate to increased 5-HT release as a result of the blockade of somatodendritic 5-HT1A receptors. The only 5-HT1A receptor antagonist that exerted antidystonic effects in hamsters was pindolol, which, however, could be related to its beta-adrenoceptor blocking action. The 5-HT1A receptor partial agonist ipsapirone exerted moderate prodystonic activity. Prodystonic activity was also determined for the mixed 5-HT1A/5-HT2 receptor agonist 5-methoxy-N,N-dimethyltryptamine, although this drug was less potent in this regard than 8-OH-DPAT. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerted prodystonic effects in mutant hamsters, which, however, were also seen after the administration of the 5-HT2 receptor antagonist ritanserin. Collectively, the results of this study demonstrate that dystonia in genetically dystonic hamsters can be affected by pharmacologic manipulation of 5-HT receptors. The data may also indicate that dystonia is not a potential clinical application for selective 5-HT1A or 5-HT2 receptor antagonists.
 ...
PMID:Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster. 858 1