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)

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

The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.
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PMID:Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor. 132 82

To explore 5-HT1A receptor responsivity in panic disorder (PD), hypothermic, neuroendocrine and behavioral responses to the selective partial 5-HT1A receptor agonist ipsapirone (IPS) were investigated in patients with primary PD and healthy controls. Fourteen patients and matched controls received a single oral dose of 0.3 mg/kg IPS or placebo under double-blind, random-assignment conditions. IPS induced hypothermia and corticotropin (ACTH)/cortisol release but had only minimal effects on behavior. Compared with controls, the patients with PD exhibited significantly attenuated thermoregulatory and neuroendocrine responses to IPS. Although the healthy subjects reported increased drowsiness and the PD patients rated themselves more nervous and less calm following administration of IPS, no consistent changes in ratings of anxiety or panic symptoms were recorded. The impaired hypothermic and ACTH/cortisol responses following 5-HT1A receptor activation reflects subsensitivity of both the pre- and post-synaptic 5-HT1A receptor-effector system, thus supporting the hypothesis that a 5-HT1A receptor-related serotonergic dysfunction may be linked to the pathophysiology of PD. Future studies of 5-HT1A receptor-effector complex function in conjunction with assessment of the responsivity of other subtypes (e.g. 5-HT2, 5-HT3) should promote the evaluation of 5-HT system integrity in anxiety disorders and its involvement in anxiolytic drug effects.
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PMID:5-HT1A receptor-effector system responsivity in panic disorder. 134 19

Repeated treatment with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) resulted in significant attenuation of 8-OH-DPAT-induced hypothermia and adrenocorticol effect in mice of both sexes, while it did not affect the 8-OH-DPAT-induced decrease in 5-hydroxyindoleacetic acid in the hypothalamus in either sex. The attenuated responses developed more rapidly in female than in male mice, indicating sex differences in the adaptive regulation of the 5-HT1A receptor-mediated responses.
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PMID:Sex difference for tolerance of 5-HT1A receptor-mediated temperature and corticosterone responses in mice. 138 74

The effect of repeated treatment (5 and 10 mg/kg, po, twice daily, 14 days) with sertraline and citalopram (antidepressants which selectively inhibit the reuptake of 5-hydroxytryptamine (5-HT)) on the responsiveness of different 5-HT receptors to their agonists, was examined in rats and mice. Sertraline and citalopram (both at a dose 5 and 10 mg/kg) antagonized (the first one more potently) the hypothermia induced in mice by 8-OH-DPAT (a 5-HT1A agonist), but not the behavioural syndrome induced in rats by this substance. The m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect) was increased by sertraline and citalopram (only in a dose of 10 mg/kg). Both antidepressants, given repeatedly (as well acutely) attenuated exploratory hypoactivity induced in rats by m-chlorophenylpiperazine (a 5-HT1C effect). L-5-HTP-induced head twitches in mice (5-HT2 effect) were antagonized dose-dependently by both repeated sertraline and citalopram. Both antidepressants (citalopram only in higher dose) reduced the fenfluramine-induced hyperthermia in rats (5-HT2 effect). The results indicate that sertraline and citalopram given repeatedly decrease the responsiveness of 5-HT1A (presynaptic) and 5-HT2 receptors but increase the responsiveness of 5-HT1B receptors to respective agonists.
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PMID:Effects of sertraline and citalopram given repeatedly on the responsiveness of 5-HT receptor subpopulations. 138 65

To study the regulation of 5-HT1A receptors in the brainstem, the region most relevant to the serotonin syndrome and to serotonin-responsive human myoclonic disorders, we chronically treated rats with various 5-HT1A agonists and labeled 5-HT1A sites with [3H]8-OH-DPAT. Daily injection for 30 consecutive days of 10 mg/kg ip 8-OH-DPAT (pre- and post-synaptic 5-HT1A agonist) significantly decreased 8-OH-DPAT-evoked flat body posture, forelimb myoclonus, and hypothermia compared to chronic vehicle injection. There was no cross tolerance to 8-OH-DPAT in rats chronically injected with ipsapirone or buspirone (presynaptic 5-HT1A agonists). However, none of the 5HT1A agonists significantly altered Bmax of brainstem 5-HT1A binding sites. Chronic injection with other drugs such as 1-propranolol, (+/-) pindolol and spiperone (5-HT1A and 5-HT2 antagonists), methysergide (5-HT1 and 5-HT2 antagonist), and agonists and antagonists at various other 5-HT receptors also had no effect on binding parameters. These data demonstrate lack of cross-tolerance between pre- and post-synaptically acting 5-HT1A agonists and absence of down-regulation of presynaptic 5-HT1A sites at doses which induced tolerance of 5-HT1A-mediated behaviors of the serotonin syndrome. They suggest changes in the post-synaptic cell rather than the receptor recognition site as the mechanism of tolerance.
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PMID:Brainstem 5-hydroxytrytamine1A binding sites are not down-regulated by agonists which induce tolerance in the rat: myoclonus and other serotonergic behaviors. 138 64

1. 8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) dose-dependently induced hypothermia in mice. 2. The 5-HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose-dependently induced hypothermia. 3. The 8-OH-DPAT temperature response was antagonized by the 5-HT1 receptor antagonists quipazine (2 mg kg-1, i.p.), (+/-)-propranolol (10 mg kg-1, i.p.). (+/-)-pindolol (5 mg kg-1, i.p.), spiroxatrine (0.5 mg kg-1, i.p.) and metitepine (0.05 mg kg-1, i.p.), but not by 5-HT2 (ketanserin) or 5-HT3 (MDL 72222, GR 38032F) receptor antagonists. 4. The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response. 5. Destruction of 5-hydroxytryptamine (5-HT)-containing neurones with the neurotoxin, 5,7-dihydroxytryptamine (75 micrograms, i.c.v.), abolished the response to 8-OH-DPAT indicating that the 5-HT1A receptors involved were located on 5-HT neurones. 6. Chronic antidepressant treatment down-regulated this 8-OH-DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down-regulation was also observed following repeated administration of 8-OH-DPAT (0.5 mg kg-1, s.c.), (+/-)-pindolol (10 mg kg-1, i.p.) and ketanserin (0.5 mg kg-1, i.p.). 7. In conclusion, these data confirm that 8-OH-DPAT-induced hypothermia is mediated by 5-HT1A autoreceptors. They also indicate that the response involves D2 receptors.The present study also shows that a wide range of antidepressant drugs down-regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.
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PMID:Characterization of 8-OH-DPAT-induced hypothermia in mice as a 5-HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants. 142 68

Intraperitoneal administration of the serotonin 5-HT1A agonist, buspirone (1-5 mg/kg), produced dose- and time-related core hypothermia that was coincident with analgesia against a thermally noxious stimulus. Surface body temperature was not altered by buspirone. The 5-HT1A antagonist, NAN-190 (2 mg/kg, s.c.), blocked both hypothermic and analgesic effects, while systemic administration of the opioid antagonist, naloxone (1 mg/kg, s.c.), did not change the pattern of buspirone-induced hypothermia or analgesia. The apparent lack of opioid involvement and the documented role of the 5-HT1A receptor system in neuroendocrine substrates of thermoregulation and pain modulation prompted study of adrenal function in these buspirone-induced effects. Buspirone (5 mg/kg, i.p.) produced significant elevations in plasma epinephrine (EPI) and corticosterone (CST). Bilateral adrenalectomy reduced both control and buspirone-elevated EPI and CST levels and attenuated the antinociceptive, but not hypothermic, effects of buspirone (1-5 mg/kg, i.p.). Administration of the phenylethanolamine-N-methyltransferase (PNMT) inhibitor, dichloromethylbenzylamine (DCMB: 25 mg/kg, i.p.) reduced basal and buspirone-elevated plasma EPI, but not CST levels. This treatment did not affect buspirone-induced hypothermia, while significantly reducing buspirone antinociception. Pretreatment with the CST synthesis inhibitor, aminoglutethemide (AG: 2 x 25 mg/kg, i.p.), reduced plasma CST levels while not significantly affecting EPI. AG pretreatment did not alter the hypothermic effects of buspirone, but attenuated antinociception produced by the highest buspirone dose. The AG-induced reductions of buspirone antinociception were less than those effects produced by DCMB treatment. These data suggest that buspirone-induced antinociception may be a non-opioid, adrenally mediated co- and/or epi-phenomenon to core hypothermia evoked by 5-HT1A receptor agonism.
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PMID:Putative mechanisms of buspirone-induced antinociception in the rat. 145 90

To investigate a possible functional interaction between 5-HT1B and 5-HT1A or 5-HT2 receptors we studied the effects of 5-HT1A selective agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone, of a 5-HT1A/5-HT2 agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and of a putative 5-HT2 agonist (+/-)1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (+/- DOI) on the 5-HT1B receptor-mediated hypothermia induced by m-trifluoromethylphenylpiperazine (TFMPP) (25 mg/kg) or m-chlorophenylpiperazine (m-CPP) (20 mg/kg) in mice. 8-OH-DPAT (1.25-5 mg/kg), gepirone (1.25-5 mg/kg), 5-MeODMT (2-8 mg/kg) and (+/-)DOI (0.5-2 mg/kg) reduced dose-dependently the TFMPP- or m-CPP-induced hypothermia. At the same time 8-OH-DPAT (2.5 and 5 mg/kg, but not 1.25 mg/kg) and gepirone (1.25-5 mg/kg) themselves decreased the body temperature in mice, while 5-MeODMT (2-8 mg/kg) and (+/-)DOI (0.5-2 mg/kg) did not affect it. The present results suggest that a functional interaction exists between 5-HT1B and 5-HT1A or 5-HT2 receptors.
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PMID:Functional interaction between 5-HT1B and 5-HT1A or 5-HT2 receptors in mice. 147 May 63

5-Hydroxytryptamine (5-HT) was injected into the rostral ventrolateral medulla (RVLM) in urethane-anaesthetized rats and its effect assessed on thermoregulatory and non-thermoregulatory cutaneous circulations by the measurement of skin surface temperatures. 5-Hydroxytryptamine (5-50 nmol) produced a dose-related fall in blood pressure (5-20 mmHg) and an increase in tail and plantar foot surface temperatures, indicative of dilatation in the underlying cutaneous circulations. If heat was not applied to the animal, the body temperature fell by 1-2 degrees C within 15-25 min. The decrease in tail and foot temperatures, produced by low frequency (25 Hz, 5 min) electrical stimulation, was antagonized by the injection of 5-HT at the site of stimulation. 5-Carboxyamidotryptamine (2.5-20 nmol) and flesinoxan (5-25 nmol) produced responses similar to 5-HT. The 5-HT2 receptor agonist, alpha-methyl 5-hydroxytryptamine (alpha-methyl 5-HT, 5.5-100 nmol) was only effective in increasing tail and plantar foot temperatures, at dose levels above 25 nmol. However, in a few sites restricted to the anterior region of the RVLM, alpha-methyl 5-HT (11 nmol) evoked a small decrease in tail and foot temperatures, indicative of a constrictor effect, without influencing resting cardiovascular parameters. The results are discussed in relation to the central mechanisms which underly the hypothermia and hyperthermia produced by 5-HT1A and 5-HT2 receptor agonists.
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PMID:Changes in the tail surface temperature of the rat following injection of 5-hydroxytryptamine into the ventrolateral medulla. 152 3


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