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)

A series of four racemic ring-substituted trans-2-(indol-3-yl)cyclopropylamine derivatives was synthesized and tested for affinity at the 5-HT1A receptor, by competition with [3H]-8-OH-DPAT in rat hippocampal homogenates, and for affinity at the agonist-labeled cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes. None of the compounds had high affinity for the 5-HT1A receptor, with the 5-methoxy substitution being most potent (40 nM). At the 5-HT2A and 5-HT2B receptor isoforms, most of the compounds lacked high affinity. At the 5-HT2C receptor, however, affinities were considerably higher. The 5-fluoro-substituted compound was most potent, with a Ki at the 5-HT2C receptor of 1.9 nM. In addition, the 1R,2S-(-) and 1S,2R-(+) enantiomers of the unsubstituted compound were also evaluated at the 5-HT2 isoforms. While the 1R,2S enantiomer had higher affinity at the 5-HT2A and 5-HT2B sites, the 1S,2R isomer had highest affinity at the 5-HT2C receptor. This reversal of stereoselectivity may offer leads to the development of a selective 5-HT2C receptor agonist. The cyclopropylamine moiety therefore appears to be a good strategy for rigidification of the ethylamine side chain only for tryptamines that bind to the 5-HT2C receptor isoform.
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PMID:Synthesis and serotonin receptor affinities of a series of trans-2-(indol-3-yl)cyclopropylamine derivatives. 983 17

[3H]5-HT revealed the presence of serotonin receptors in cultured rat sensory neurons. [3H]5-CT binding was inhibited by cyanopindolol with an IC50 of 0.87 +/- 0.30 nM, suggesting the expression of the 5-HT1B receptor in these neurons. The presence of 5-HT1B receptors was confirmed by the displacement of [125I]Iodocyanopindolol binding by cyanopindolol with an IC50 of 2.43 +/- 0.81 nM. 5-HT1B receptors are the predominant type of serotonin receptors labeled by [3H]5-HT in cultured DRG neurons, representing approximately 60% of the specific [3H]5-HT binding sites. In addition, 5-HT1D and 5-HT2A receptor binding was also found in these neurons. RT-PCR analysis of RNA isolated from embryonic sensory neurons in culture confirmed the expression of 5-HT1B, 5-HT1D and 5-HT2A receptor mRNA. It also demonstrated the presence of 5-HT1F, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A and 5-HT5B receptor mRNA and the absence of 5-HT1A, 5-HT1E, 5-HT2B, 5-HT6 and 5-HT7 mRNA. The identification of multiple subtypes of serotonin receptors expressed in cultured embryonic sensory neurons suggests that DRG neuronal cultures may be an excellent model to examine the direct effects of serotonin on the activity of these sensory neurons.
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PMID:Multiple subtypes of serotonin receptors are expressed in rat sensory neurons in culture. 986 1

Anxiety disorders are heterogeneous and existing animal models do not discriminate specific types of anxiety. The elevated T-maze is being developed to fulfill this purpose. The apparatus consists of three elevated arms, one enclosed and two open. Inhibitory avoidance--representing learned fear--is measured by recording the time taken to leave the enclosed arm in three consecutive trials. Unconditioned fear is evaluated by recording the time to escape from the open arm. Restraining the animals at the end of the enclosed arm for 30 s did not change the first (baseline) withdrawal latency, indicating that rats are not escaping from the experimenter's hand. In addition, rats trained in a T-maze with the three arms enclosed did not show the usual increase in withdrawal latency over the three consecutive trials. These results indicate that open arm experience, not handling, motivates inhibitory avoidance learning. The same experiment also showed that the latency to leave the open arm did not undergo habituation over five consecutive trials, thereby providing evidence of an aversive motivation for this response. The anxiolytic agents diazepam (benzodiazepine), buspirone and ipsapirone (5-HT1A agonists) as well as ritanserin (5-HT2 antagonist) selectively impaired inhibitory avoidance while leaving one-way escape unchanged. Similar results were obtained with three putative anxiolytics: the 5-HT2B/2C antagonists SB 200646A and SER 082, and the 5-HT2A antagonist SR 46349B. However, RP 62203, another 5-HT2A antagonist, was ineffective on both tasks. In contrast to the above anxiolytics, the anxiogenic agents yohimbine, TFPP and mCPP facilitated inhibitory avoidance. Escape was not affected by yohimbine, but was moderately attenuated by the two 5-HT2C/2B agonists. The 5-HT releaser and uptake inhibitor D-fenfluramine tended to enhance inhibitory avoidance, while impairing one-way escape in a dose-dependent way. The antidepressant clomipramine also had an anxiogenic-like effect on inhibitory avoidance, but did not affect escape from the open arm. Conversely, the phenethylamine hallucinogen ALEPH 2 did not affect inhibitory avoidance while impairing escape. Nevertheless, the similar compound and 5-HT2A agonist DOI was devoid of any effect. Also ineffective were the psychomotor stimulants D,L-amphetamine and caffeine, the reversible monoaminoxidase-A inhibitor moclobemide and the neuroleptic haloperidol. Finally, micro-injection into the dorsal raphe nucleus of two drugs that stimulate 5-HT neurons, the excitatory amino acid kainic acid and the benzodiazepine inverse agonist FG 7142, facilitated inhibitory avoidance. Kainate also significantly impaired escape. In contrast, intra-raphe 8-OH-DPAT, which inhibits 5-HT neurons, selectively impaired inhibitory avoidance in a manner similar to systemically administered anxiolytics. These behavioral and pharmacological results support the view that inhibitory avoidance in the elevated T-maze may be related to generalized anxiety disorder, while one-way escape may be associated with panic disorder.
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PMID:The elevated T-maze as an experimental model of anxiety. 988 16

The 5-HT2B receptor agonist, BW 723C86 (10, 30(mg/kg i.p. 30 min pre-test), increased the number of punishments accepted in a rat Vogel drinking conflict paradigm over 3 min, as did the benzodiazepine anxiolytics, chlordiazepoxide (2.5-10 mg/kg p.o. 1 h pre-test) and alprazolam (0.2-5 mg/kg p.o. 1 h pre-test), but not the 5-HT2C/2B receptor agonist, m-chlorophenylpiperazine (mCPP, 0.3-3 mg/kg i.p) or the 5-HT1A receptor agonist, buspirone (5-20 mg/kg p.o. 1 h pre-test). The effect of BW 723C86 was unlikely to be secondary to enhanced thirst, as BW 723C86 did not increase the time that rats with free access to water spent drinking, nor did it reduce sensitivity to shock in the apparatus. The anti-punishment effect of BW 723C86 was opposed by prior treatment with the 5-HT2/2B receptor antagonist, SB-206553 (10 and 20 mg/kg p.o. 1 h pre-test), and the selective 5-HT2B receptor antagonist, SB-215505 (1 and 3 mg/kg p.o. 1 h pre-test), but not by the selective 5-HT2C receptor antagonist, SB-242084 (5 mg/kg p.o.), or the 5-HT1A receptor antagonist, WAY 100635 (0.1 or 0.3 mg/kg s.c. 30 min pre-test). Thus, the anti-punishment action of BW 723C86 is likely to be 5-HT2B receptor mediated. This is consistent with previous reports that BW 723C86 exhibited anxiolytic-like properties in both the social interaction and Geller-Seifter conflict tests.
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PMID:Anxiolytic-like actions of BW 723C86 in the rat Vogel conflict test are 5-HT2B receptor mediated. 988 83

The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds.
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PMID:Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine. 1009 Jul 93

5-Hydroxytryptamine (5-HT) has been implicated in pulmonary hypertension, hypoxic pulmonary vasoconstriction, and the pulmonary side-effects of some drugs. 5-HT contracts bovine, ovine, canine, caprine, feline, rabbit, guinea-pig and rat isolated pulmonary arteries mainly by activation of 5-HT2A receptors but relaxes porcine pulmonary artery through activation of endothelial 5-HT2B receptors. Pharmacological responses of the pulmonary veins to 5-HT have been less studied and comprise both contraction (bovine, canine, feline, equine, rabbit) and relaxation (ovine, caprine). Functional and radioligand binding studies in human isolated intrapulmonary arteries and veins have demonstrated a mixed population of 5-HT1B/1D and 5-HT2A receptors mediating vasoconstriction but no evidence of involvement of 5-HT1A, 5-HT3 and 5-HT4 receptors. Remarkable differences exist in the in vitro pulmonary vasoreactivity to 5-HT and related drugs in humans compared with other mammals. Therefore, the use of human tissues is to be preferred to study pathophysiological responses of pulmonary circulation with clinical relevance.
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PMID:Species differences in the responses of pulmonary vascular preparations to 5-hydroxytryptamine. 1021 31

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.
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PMID:Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors. 1063 Jul 30

The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/alpha1/H1 antagonist ketanserin analogues QF 0303B, QF 0307B, QF 0311B, QF 0313B were studied in anaesthetized normotensive rats (ANR) and in isolated rubbed rat aorta (IRRA). In ANR, 0.2 mg x kg(-1) i.v. of each compound produced a rapid, remarkable but short-lasting fall in mean arterial blood pressure (MAP) accompanied by bradycardia. All compounds significantly modified the pressor effects induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). In IRRA, the compounds inhibited NA- and 5-HT-induced contractions in a competitive fashion. Furthermore, the analogues displayed lower H1-antagonist activity than ketanserin. Compounds tested showed low 5-HT2B affinity and no activity at muscarinic, nicotinic, or 5-HT3 receptors, nor any marked ability to produce smooth muscle relaxation via calcium entry blockade. There is a significant correlation between hypotension reached and inhibition of the 5-HT-induced pressor responses (but not for NA). A certain degree of correlation was observed between hypotensive effect endurance vs. alpha1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT1A receptor blockade and the duration of the effect is better attributed to an alpha1 adrenoceptor blockade.
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PMID:Study of the in vivo and in vitro cardiovascular effects of four new analogues of ketanserin: implication of 5-HT2A and alpha1 adrenergic antagonism in their hypotensive effect. 1082 64

Serotonin (5-hydroxytryptamine, 5-HT) has been shown to play a role in immunoregulation; however, little is known about specific subtypes of 5-HT receptors involved in peripheral immunomodulation. In the present study we used RT-PCR methods to examine the mRNA expression of 5-HT receptors in the cells of lymphoid tissues of the rat. All 13 rat 5-HT receptor genes cloned so far were examined in ex vivo isolated spleen, thymus, and peripheral blood lymphocytes, as well as in mitogen-stimulated spleen cells. Positive signals were obtained for 5-HT1B, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT6, and 5-HT7 receptor mRNAs in all three compartments. Mitogen (ConA and PWM) stimulated cells additionally expressed mRNA corresponding to the 5HT-3 receptor subtype. In contrast, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT4, 5-HT5A, and 5-HT5B mRNAs were not detected in any of the examined cell populations. These results may be useful as a starting point for future functional studies on immunomodulatory effects of 5-HT and may help to understand conflicting serotonergic effects on immune functions as found in the literature.
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PMID:mRNA expression of serotonin receptors in cells of the immune tissues of the rat. 1097 Jun 81

The effects of serotonin (5-HT) receptor ligands on the MK 212 (6-chloro-2[1-piperazinyl]pyrazine) discriminative stimulus and quipazine-induced head twitches were studied in rats. 5-HT1A (8-OH-DPAT) and preferential 5-HT2A (DOI) receptor agonists did not generalize to the discriminative stimulus. The 5-HT2B/2C-receptor antagonist, SB 206553 (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2 ,3-f]indole), and the 5-HT2A/2C-receptor antagonist, ritanserin, acted as potent antagonists, whereas the 5-HT2A-receptor antagonist, MDL 100.151 ([(+/-)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4- piperidine-methanol), produced minor and inconsistent inhibition. SB 206553 was a weak antagonist against quipazine-induced head twitches, whereas MDL 100.151 and ritanserin were potent antagonists. This suggests that the MK 212 discriminative stimulus is mediated by 5-HT2C receptors, while quipazine-induced head twitches are mediated primarily by 5-HT2A receptors. The effects on quipazine-induced head twitches were comparable to previously published effects on the DOI discriminative stimulus. 5-HT2A- and 5-HT2C-receptor antagonistic potencies of clozapine, olanzapine, risperidone, sertindole and ziprasidone were compared in the same models. Clozapine showed similar potencies in both models, while sertindole, olanzapine and risperidone inhibited quipazine-induced effects more potently than the MK 212 discriminative stimulus. Ziprasidone exerted a minor preference for 5-HT2A- compared to 5-HT2C-receptor-mediated effects. The ratio between in vivo inhibitory potencies at 5-HT2A and 5-HT2C receptors did not correlate with corresponding ratios from in-vitro affinity and ex-vivo occupancy studies in the literature.
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PMID:In-vivo assessment of 5-HT2A and 5-HT2C antagonistic properties of newer antipsychotics. 1110 83


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