Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

1. We investigated some neurochemical properties of a novel benzamide, YM-43611, [(S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-cyclopropylcarbonylamino+ ++-2- methoxybenzamide] in comparison with putative D2-like receptor antagonists using both rat and human cloned dopamine D2-like receptors in vitro. 2. Receptor binding studies revealed that YM-43611 had appropriately potent affinities for both rat and human D2-like receptors, with moderate selectivity for D3 receptors and high selectivity for D4 receptors over D2 receptors (Ki values (nM) for rat receptors: D2, 165; D3, 35.5; D4, 1.85, and for human receptors: D2, 42.9; D3, 11.2; D4, 2.10). 3. YM-43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D1, D5, alpha(1), alpha(2), beta, 5-HT1A, 5-HT2A, 5-HT3, H1, M1 and M2 receptors. 4. Dopamine stimulated low-Km GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D2-like receptor subtype. This response to dopamine of low-Km GTPase activity was inhibited by use of putative D2-like receptor antagonists. YM-43611 showed a moderate selectivity for D3 receptors (Ki = 45.5 nM) and a high selectivity for D4 receptors (Ki = 3.28 nM) over D2 receptors (Ki = 70.6 nM). 5. Dopamine inhibited forskolin-stimulated adenylate cyclase in intact CHO cells expressing the human D2-like receptor subtype. YM-43611 shifted the inhibition curve of dopamine on respective D2-like receptor subtype-mediated cyclic AMP formation to the right in a parallel fashion, showing a pA2 value of 7.42 (38.1 nM) for D2 receptors, a pKB value of 8.06 (8.68 nM) for D3 receptors, and a pA2 value of 8.42 (3.77 nM) for D4 receptors. 6. YM-43611 but not the other D2-like receptor antagonists exhibited good selectivity with respect to dual antagonism for D3 and D4 receptors in both receptor binding and functional assays. 7. These results indicate that YM-43611 is a novel D2-like receptor antagonist with high potency and selectivity for both D3 and D4 receptors. YM-43611 is therefore expected to be valuable in exploration of the physiological role of D3 and D4 receptors.
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PMID:In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors. 873 69

The role of 5-HT(1B/1D) receptors in modulating extracellular 5-hydroxytryptamine (5-HT) levels in the guinea pig was investigated with the non-selective 5-HT(1B/1D) receptor inverse agonist, methiothepin, and the selective 5-HT(1B/1D) receptor partial agonists, GR 127935 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5-me thyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-4-carboxamide) and GR 125743 (n-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-3-methyl-4-(4-pyri dinyl)benzamide). Extracellular 5-HT levels were measured using the technique of brain microdialysis, in the frontal cortex of the freely moving guinea-pig. Extracellular 5-HT was tetrodotoxin sensitive and calcium dependent, and increased when perfused with a high concentration of K+. In addition, extracellular 5-HT levels were lowered by the 5-HT(1B/1D) receptor agonist, sumatriptan, and the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, while perfusion of the selective serotonin re-uptake inhibitor, paroxetine, increased 5-HT in a concentration-dependent manner. Perfusion of methiothepin, GR 127935 and GR 125743 into the frontal cortex caused significant but transient increases of extracellular 5-HT. However, systemic administration of methiothepin, GR 127935 and GR 125743, at 0.3 mg/kg i.p., produced significant decreases in extracellular 5-HT, to minima of 27 +/- 3%, 31 +/- 12% and 27 +/- 13% of basal, respectively. The increase of extracellular 5-HT, following 5-HT(1B/1D) receptor inverse and partial agonist perfusion into the frontal cortex, was probably a consequence of attenuation of an endogenous 5-HT tone at terminal 5-HT autoreceptors. The unexpected decrease in 5-HT levels following systemic administration may be a result of additional attenuation of endogenous 5-HT tone at cell body autoreceptors in the raphe. Such an increase in local 5-HT levels could then stimulate 5-HT1A receptors to inhibit cell firing and hence decrease 5-HT levels in the terminal regions. This was confirmed when co-administration of the 5-HT1A receptor antagonist, WAY 100635, significantly attenuated the GR 127935 decrease in 5-HT.
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PMID:The role of 5-HT(1B/1D) receptors in the modulation of 5-hydroxytryptamine levels in the frontal cortex of the conscious guinea pig. 917 51

The actions of several serotonergic ligands in use or under development for the treatment of migraine headaches were examined at recombinant human 5-HT1A receptors stably expressed in Chinese Hamster Ovary cells. Affinities (K(i)s) at this site were determined in competition binding experiments with [3H]-8-OH-DPAT ([3H](+/-)8-hydroxy-N,N-dipropylaminotetralin), whilst agonist efficacy was measured by stimulation of [35S]-GTP gamma S (guanylyl-5'-[gamma[35S]thio]-triphosphate) binding. Of the prophylactic antimigraine drugs tested, methysergide and lisuride behaved as efficacious agonists (Emax > or = 90% relative to 5-HT) whereas pitozifen and (-)propranolol acted as a partial agonist (60%) and an antagonist, respectively. This suggests that there is no correlation between agonism at 5-HT1A receptors and prophylactic antimigraine action. In contrast, serotonin, dihydroergotamine, sumatriptan, naratriptan and alniditan, which are effective in acute interruption of migraine attacks, each displayed high efficacy (Emax = 100, 100, 92.6, 79.3, 79.1% respectively) and marked affinity (Ki = 18.7, 0.6, 127, 26.4 and 3.0 nM respectively) at 5-HT1A receptors. EC50 values for agonist stimulation of [35S]-GTP gamma S binding correlated with respective Ki values at 5-HT1A receptors (r = 0.93) and the stimulation of [35S]-GTP gamma S binding by these compounds was antagonised by the selective 5-HT1A antagonist WAY 100,635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide; 100 nM). These data suggest that agonism at 5-HT1A receptors may be involved in some actions of drugs used in acute antimigraine therapy. In comparison with the above compounds, novel ligands targeted at 5-HT1B/1D receptors, such as GR125,743 (N-[4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl] -3-methyl-4-(4-pyridyl)benzamide) and GR 127,935 (N-[4-methoxy-3-(4-methylpiperazin-1-yl)-phenyl]-2'-methyl-4'-(5-m ethyl-1, 2,4-oxadiazol-3-yl)-biphenyl-4-carboxamide), only weakly activated [35S]-GTP gamma S binding (32.4 and 32.1% efficacy) and displayed moderate affinity at 5-HT1A receptors (Kis 53.1 and 49.8 nM) suggesting that they constitute useful tools to differentiate 5-HT1A and 5-HT1B/1D receptor-mediated actions. In conclusion, the present data indicates that several antimigraine agents exhibit marked 5-HT1A receptor activity and that although this is unlikely to be important for prophylactic action it may be relevant to the ancilliary properties of drugs used for acute migraine treatment.
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PMID:Agonist activity of antimigraine drugs at recombinant human 5-HT1A receptors: potential implications for prophylactic and acute therapy. 920 51

Recent studies have established that the expression of defensive rage behavior in the cat is mediated over a descending pathway from the medial hypothalamus to the dorsolateral quadrant of the midbrain periaqueductal gray matter (PAG). The present study was designed to determine the roles played by 5-HT1A and 5-HT2/1C receptors in this region of PAG in modulating defensive rage behavior elicited from the cat's medial hypothalamus. Monopolar stimulating electrodes were implanted into the medial hypothalamus from which defensive rage behavior could be elicited by electrical stimulation. During the course of the study, the 'hissing' component of the defensive rage response was used as a measure of defensive rage behavior. Cannula-electrodes were implanted into sites within the PAG from which defensive rage could also be elicited by electrical stimulation in order that 5-HT compounds could be microinjected into behaviorally identifiable regions of the PAG at a later time. Microinjections of the selective 5-HT1A agonist, (+)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OHDPAT) (50 pmol, 2.0 and 3.0 nmol), into the PAG suppressed the hissing response in a dose-dependent manner. Administration of the selective 5-HT1A antagonist, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) (1.5 and 3.0 nmol), blocked the suppressive effects of 8-OHDPAT upon hissing. In contrast, microinjections of the 5-HT2/1C receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+)-DOI hydrochloride) (0.01, 1.0 and 1.5 nmol) facilitated the occurrence of hissing elicited from the medial hypothalamus in a dose-dependent manner. Immunohistochemical analysis revealed the presence of 5-HT axons and preterminals throughout the PAG, and in particular, in its dorsolateral aspect which receives major inputs from the medial hypothalamus in association with defensive rage behavior. The overall findings of the study provide evidence that activation of 5-HT1A and 5-HT2/1C receptors within the midbrain PAG differentially modulate the expression of defensive rage behavior elicited from the medial hypothalamus of the cat.
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PMID:Serotonin 5-HT1A and 5-HT2/1C receptors in the midbrain periaqueductal gray differentially modulate defensive rage behavior elicited from the medial hypothalamus of the cat. 931 92

Serotonin (5-HT) is generally inhibitory to male rat sexual behavior. However, the 5-HT1A agonist 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), injected either systemically or into the medial preoptic area (MPOA), facilitates ejaculation. Three experiments were conducted to test the effects of 8-OH-DPAT on 5-HT and dopamine (DA) neurotransmission in the MPOA, a very important site for the control of male sexual behavior. In Experiment 1, systemically injected 8-OH-DPAT (0.4 mg/kg) decreased extracellular 5-HT levels in the MPOA as measured by in vivo microdialysis. In Experiment 2, 8-OH-DPAT (500 microM) administered directly into the MPOA via reverse dialysis increased extracellular levels of both DA and 5-HT; pretreatment with the selective 5-HT1A antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-ben benzamide hydrochloride (p-MPPI) failed to prevent 8-OH-DPAT's stimulatory effects on DA and 5-HT levels in the MPOA. In Experiment 3, 8-OH-DPAT (8 microg) co-injected with 5,7-dihydroxytryptamine (5,7-DHT; 6 microg) prevented neurotoxic depletion of 5-HT in the site of injection (MPOA). Because systemic and MPOA injections of 8-OH-DPAT resulted in opposite effects on extracellular 5-HT in the MPOA, yet both can facilitate ejaculation, these data suggest that moderate changes in 5-HT in the MPOA may have relatively little influence on male copulatory behavior. Instead, the facilitative effects of 8-OH-DPAT in the MPOA on male copulatory behavior may result, at least in part, from stimulatory effects of 8-OH-DPAT on DA transmission. Facilitative effects of systemic injections of 8-OH-DPAT may result from decreased 5-HT release in several sites.
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PMID:8-OH-DPAT influences extracellular levels of serotonin and dopamine in the medial preoptic area of male rats. 959 1

The benzofurane (+)-S 14297, the benzamide nafadotride, the aminoindane U 99194 and the arylpiperazine GR 103,691 have been proposed as "selective" antagonists at dopamine D3 vs. D2 receptors. Herein, we compared their in vitro affinities and in vivo actions to those of the aminotetralin D3 antagonists (+)-AJ 76 and (+)-UH 232. Affinities at recombinant, human (h)D3 and/or hD2 sites were determined by employing the mixed D2/D3 antagonist [125I]-iodosulpride and the preferential D3 ligands [3H]-(+)-PD 128, 907 and [3H]-(+)-S 14297. [3H]-(+)-PD 128,907, [3H]-(+)-S 14297 and [125I]-iodosulpride yielded an essentially identical pattern of displacement at D3 sites, which suggests that they recognize the same population of receptors. The rank order of potency (Ki values in nM vs. [3H]-(+)-PD 128,907) was GR 103,691 (0.4) approximately nafadotride (0.5) > haloperidol (2) approximately (+)-UH 232 (3) approximately (+)-S 14297 (5) > (+)-AJ 76 (26) > U 99194 (160). The rank order of preference (Ki ratio, D2:D3) for D3 receptors (labeled by [3H]-PD 128,907) vs. D2 sites (labeled by [125I]-iodosulpride) was (+)-S 14297 (61) approximately GR 103,691 (60) > U 99194 (14) > nafadotride (9) approximately (+)-UH 232 (8) approximately (+)-AJ 76 (6) > haloperidol (0.2). (+)-S 14297 and GR 103,691 also showed greater than 100-fold selectivity at dopamine hD3 vs. hD4 and hD1 sites. However, GR 103,691 showed marked affinity for serotonin1A receptors (5.8 nM) and alpha-1 adrenoceptors (12.6 nM). In vivo, all antagonists except GR 103,691 prevented the induction of hypothermia by (+)-PD 128,907 (0.63 mg/kg s.c.) and a further preferential D3 agonist, (+)-7-OH-DPAT (0.16 mg/kg s.c.). On the other hand, haloperidol, (+)-AJ 76, (+)-UH 232 and nafadotride all induced catalepsy in rats, whereas (+)-S 14297, U 99194 and GR 103,691 were inactive. Haloperidol, (+)-AJ 76, (+)-UH 232, nafadotride and (weakly) U 99194 also enhanced prolactin secretion and striatal dopamine synthesis, whereas (+)-S 14297 and GR 103,691 were inactive. However, despite its high affinity at 5-HT1A receptors and alpha-1 adrenoceptors, both of which are present on raphe-localized serotonergic neurons, GR 103,691 (0.5 mg/kg i.v.) failed to influence their basal firing rate or the inhibition of their electrical activity by the 5-HT1A agonist (+/-)-8-OH-DPAT (0.005 mg/kg i.v.), a result that casts doubt on its activity in vivo. In conclusion, both (+)-S 14297 and GR 103,691 are markedly selective ligands that permit the characterization of actions at hD3 vs. hD2 receptors in vitro, but (+)-S 14297 appears to be of greater utility for the evaluation of their functional significance in vivo. Nevertheless, to develop a better understanding of the respective roles of dopamine D3 and D2 receptors, we need additional, chemically diverse antagonists of improved potency and selectivity.
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PMID:A comparative in vitro and in vivo pharmacological characterization of the novel dopamine D3 receptor antagonists (+)-S 14297, nafadotride, GR 103,691 and U 99194. 976 37

A series of new 1-aryl-4-alkylpiperazines containing a terminal benzamide fragment or a tetralin-1-yl nucleus on the alkyl chain were synthesized and tested for binding at cloned human dopamine D4 and D2 receptor subtypes. A SAFIR (structure-affinity relationship) study on this series is herein discussed. The most relevant D4 receptor affinities were displayed by N-[omega-[4-arylpiperazin-1-yl]alkyl]-methoxybenzamides (compounds 5, 16-20), their IC50 values ranging between 0.057 and 7.8 nM. Among these, N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (17) emerged since it exhibited very high affinity for dopamine D4 receptor (IC50 = 0.057 nM) with selectivity of >10 000 for the D4 versus the D2 receptor; compound 17 was also selective versus serotonin 5-HT1A and adrenergic alpha1 receptors.
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PMID:N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: a potent and selective dopamine D4 ligand. 982 59

The effects of serotonin1B [5-hydroxytryptamine1B (5-HT1B)] receptor activation on cocaine reinforcement were investigated using intravenous cocaine self-administration by rats. The 5-HT1B receptor agonists 5-methoxy-3-1,2,3,6-tetrahydro-4-pyridinyl-1H-indole (RU 24969) (0.3-3 mg/kg), 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94,253) (0.3-3 mg/kg), and 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3, 2-b]pyridine (CP 93,129) (3 and 10 micrograms, i.c.v.) each dose-dependently reduced the self-administration of a cocaine dose on the descending limb of the fixed-ratio 5 (FR-5) cocaine dose-effect function, in a manner similar to the effect produced by increasing the unit dose of cocaine. In addition, each of these 5-HT1B agonists lowered the threshold dose of cocaine that supported self-administration. These results are consistent with a 5-HT1B agonist-induced potentiation of cocaine reinforcement. On a progressive ratio schedule of reinforcement, RU 24969 and CP 94,253 dose-dependently (0.3-3 mg/kg) increased the highest completed ratio for cocaine self-administration, again by producing behavioral alterations similar to those induced by increasing the unit dose of cocaine. The effect of CP 94,253 was dose-dependently blocked by the 5-HT1B/1D receptor partial agonist 2'-methyl-4'-(5-methyl[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid[4-methodoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide (GR 127, 935) (0.3-10 mg/kg) but was unaffected by the 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl- benzamide (p-MPPI; 1-10 mg/kg). Self-administration behavior was not maintained when either RU 24969 or CP 94,253 was substituted for cocaine, indicating that these 5-HT1B agonists do not produce significant reinforcing effects alone. Together, these findings indicate that 5-HT1B receptor stimulation facilitates the reinforcing properties of cocaine. These results are in opposition to recent findings with 5-HT1B receptor knock-out mice and may have important ontogenic implications in the area of drug abuse research.
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PMID:Serotonin1B receptor stimulation enhances cocaine reinforcement. 982 62

Several structural analogues of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 1), a representative of a series of 2-aminotetralin-derived benzamides with potential atypical antipsychotic properties, were synthesized and evaluated for their ability to bind to dopamine D2A, D3, and serotonin 5-HT1A receptors in vitro. The structure affinity relationships revealed that the aromatic ring of the benzamide moiety of 1 contributes to the high affinities for all three receptor subtypes. Furthermore, 1 may interact with the dopamine D2 and D3 receptors through hydrogen bond formation with its carbonyl group. Investigation of the role of the amide hydrogen atom by amide N-alkylation was not conclusive, since conformational aspects may be responsible for the decreased dopaminergic affinities of the N'-alkylated analogues of 1. The effects of the amide modifications on the serotonin 5-HT1A receptor affinity were less pronounced, suggesting that the benzamidoethyl side-chain of 1 as a whole enhances the affinity for this receptor subtype probably through hydrophobic interactions with an accessory binding site. The structural requirements for the substituents at the basic nitrogen atom supported the hypothesis that the 2-aminotetralin moieties of the 2-aminotetralin-derived substituted benzamides may share the same binding sites as the 2-(N,N-di-n-propylamino)tetralins.
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PMID:Structural analogues of 5-OMe-BPAT: synthesis and interactions with dopamine D2, D3, and serotonin 5-HT1A receptors. 1042 81

Molecular modeling studies were undertaken in order to elucidate the possible dopamine D2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-BPAT, 1). For this purpose, a combination of indirect molecular modeling and direct construction of the seven transmembrane (7TM) domains of the receptors was employed in a stepwise, objective manner. Pharmacophore models and corresponding receptor maps were identified by superimposing selected sets of receptor agonists in their presumed pharmacologically active conformations, while taking the conformational freedom of the ligands into account. The 7TM models were then constructed around the agonist pharmacophore models, by adding the TM domains one-by-one. Initially, the relative positions of TM3, TM4, and TM5 were determined using the three-dimensional structure of bacteriorhodopsin, but subsequently the orientations of all TM domains were adjusted in order to mimic the topology of the TM domains of rhodopsin. The presumed dopamine D2 receptor binding conformations of (S)- and (R)-1 were determined by using the semirigid dopamine D2 receptor antagonist N-benzylpiquindone as a template for superposition. Similarly, the selective serotonin 5-HT1A receptor agonist flesinoxan was employed for identifying the serotonin 5-HT1A receptor binding conformations of the enantiomers of 1. After docking of the presumed pharmacologically active conformations in the 7TM models and subsequent optimization of the binding sites, specific interactions between the ligands and the surrounding amino acid residues, consistent with the structure-activity relationships, were observed. Thus, both enantiomers of 1 bound to the dopamine D2 receptor model in a similar fashion: a reinforced electrostatic interaction was present between the protonated nitrogen atoms and Asp114 in TM3; their carbonyl groups accepted a H-bond from Ser121 in TM3; their amide NH groups acted as H-bond donor to Tyr416 in TM7; and their benzamide phenyl rings were involved in a hydrophobic edge-to-face interaction with Trp386 in TM6. Differences were observed in the orientations of the 2-aminotetralin moieties, which occupied the agonist binding site. Whereas the (S)-enantiomer could form a H-bond between its 5-methoxy substituent and Ser193 in TM5, the (R)-enantiomer could not, which may account for the differences in their intrinsic efficacies at the dopamine D2 receptor. In the serotonin 5-HT1A receptor model, the benzamide phenyl rings of both enantiomers were involved in hydrophobic face-to-face interactions with Phe112 in TM3, while their protonated nitrogen atoms formed a reinforced electrostatic interaction with Asp116 in TM3. Consistent with the structure-affinity relationships of 1, the amide moieties were not involved in specific interactions. Both enantiomers of 1 could form a hydrogen bond between their 5-methoxy substituent and Thr200 in TM5, which may account for their full serotonin 5-HT1A receptor agonist properties.
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PMID:Molecular modeling of the dopamine D2 and serotonin 5-HT1A receptor binding modes of the enantiomers of 5-OMe-BPAT. 1053 Sep 28


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