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)

A series of 1-, 3-, and 4-substituted analogs to the potent 5-HT1A against 8-(dipropylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (5) were prepared and tested in vitro at 5-HT1A, 5-HT1D alpha, 5-HT1D beta, D2, and D3 receptors and in vivo for agonist activity in the 5-HTP and DOPA accumulation assays in reserpine-pretreated rats. Some of the compounds were resolved. The substituents used in the 1-position were chosen from a principal component analysis (PCA) plot constructed from both tabulated variables and variables calculated by semiempirical methods (PM3) and molecular mechanics software (MMX). Among the analogs prepared, some, e.g., compound 21, were equipotent to compound 5 with respect to 5-HT1A effects. All compounds were more or less selective for the 5-HT1A receptor, but many of the compounds displayed higher affinities for 5-HT1D alpha than for 5-HT1D beta receptors.
 ...
PMID:Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 1. Effects of substituents in the aromatic system on serotonin and dopamine receptor subtypes. 778 52

A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA. Nearly all of the compounds prepared for this study were exceedingly potent at the 5-HT1A receptor, although most also displayed significant affinity for the dopamine D-2 receptor. A strong preference for the 5-HT1D alpha over the 5-HT1D beta receptor was also apparent. An analog bearing a butylglutarimide side chain, S-7k, was extremely selective for the 5-HT1A receptor. Although this compound possessed a Ki of 0.6 nM, it elicited only modest changes in 5-HTP brain levels. However, this compound did not appear as an antagonist when tested in a cyclic-AMP-based intrinsic activity assay.
 ...
PMID:Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 2. Effects of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology. 778 53

To gain further insight into the operation of 5-HT autoreceptor-mediated feedback control of 5-HT biosynthesis in serotonergic nerve terminal areas, the effect of the 5-HT1B and the 5-HT1A receptor agonists, TFMPP and 8-OH-DPAT, respectively, were investigated in the rat central nervous system (CNS) using in vivo and in vitro neurochemical approaches. TFMPP suppressed 5-HT synthesis (5-HTP accumulation after decarboxylase inhibition) both in vivo and in vitro. In vivo, the 5-HT synthesis-suppressing effect of the drug (3.0 mg/kg, s.c.) proved resistant to either acute hemitransection or reserpine (5 mg/kg, i.p.; 90 min before) pretreatment. In vitro, in cortical, hippocampal and striatal slice preparations, TFMPP (0.1-10 microM) decreased 5-HT synthesis under basal and stimulated (30 mM K+) conditions, an effect which was unaltered by prior in vivo reserpine-induced 5-HT depletion but was attenuated in the presence of 5-HT1B receptor antagonists such as methiothepin, cyanopindolol or propranolol. The 8-OH-DPAT (0.1 mg/kg, s.c.)-induced decrease of 5-HT synthesis in vivo was abolished by hemitransection but resistant to acute reserpine pretreatment; 8-OH-DPAT (10 microM) did not decrease 5-HT synthesis in vitro. In conclusion, the present study confirms the importance of 5-HT autoreceptors in the feedback control of nerve terminal 5-HT biosynthesis. Specifically, our data indicate: (1) that the reduction of rat brain 5-HT synthesis after TFMPP is mediated by 5-HT1B autoreceptors located on the serotonergic axon terminals, and (2) that the effect is directly mediated and occurs independently of 5-HT neuronal firing and intact monoamine stores.
 ...
PMID:Evidence for 5-HT autoreceptor-mediated, nerve impulse-independent, control of 5-HT synthesis in the rat brain. 778 57

This study was performed in rats to determine if serotonin and its receptors are involved in the increase of gastric emptying (GE) induced by benzodiazepine (BZ) withdrawal. GE was measured with a test meal (2 ml) containing 1 microCi/ml of 51Cr sodium chromate administered in rats, either previously receiving injections with diazepam (15 mg/kg/day i.p.) or with DMSO (0.9 ml/day i.p.) during 7 days. On the 8th day, animals received the different serotonin (5-HT) agonists or antagonists, and flumazenil (BZ antagonist; 15 mg/kg i.p.) 30 and 15 min, respectively, before the test meal. Methiotepin (5-HT1 antagonist) either i.p. (0.1-1 mg/kg) or intracerebroventricularly (10 micrograms/kg) had no effect on the increase of GE induced by precipitated-withdrawal. 8-OH-DPAT (5-HT1A agonist) administered i.c.v. (1-10 micrograms/kg) dose dependently reduced GE increase. Administered i.p. (0.1 mg/kg), it blocked GE increase in control and diazepam-withdrawn rats. Ritanserin (5-HT2 antagonist) antagonized GE increase only when administered i.p. (0.1 mg/kg). Granisetron (5-HT3 antagonist) was active both i.p. (0.01-0.1 mg/kg) and intracerebroventricularly (1-10 micrograms/kg). Administered intracerebroventricularly (1 microgram/kg) in diazepam-treated rats, 5-HTP mimicked the effect of flumazenil. It is concluded that diazepam-withdrawal increases GE by stimulating central release of 5-HT and/or central activation of 5-HT neurons. At least central 5-HT3 receptors, and in less extend, peripheral 5-HT2 receptors are involved in this mechanism.
 ...
PMID:Benzodiazepine-withdrawal-induced gastric emptying disturbances in rats: evidence for serotonin receptor involvement. 779 Nov 33

8-OH-DPAT, a selective 5-HT1A agonist, produced a hypothermic response in mice at a dosage of 0.5 mg/kg. Administration of corticosterone-21-acetate (0.5, 5 and 50 mg/kg, daily for 3 and 10 days) produced a dose-dependent attenuation of this hypothermic response in mice. When all controls and corticosterone treated mice were retested, 14 days after initial testing, they did not differ in the hypothermic responses induced by 8-OH-DPAT. Mice treated with aldosterone (50 mg/kg), dexamethasone (50 mg/kg) and the specific type 2 corticosteroid receptor agonist, 11b,17b-dihydroxy-21-methyl-17a-pregna-1,4,6-trien-20-yn+ ++-3-one (RU26988, 30 mg/kg) for 10 days, did not differ from vehicle treated controls in the hypothermic response to 8-OH-DPAT. Mice administered corticosterone-21-acetate (30 mg/kg, daily) for 10 days displayed a motor behavioural syndrome, which was not seen in controls, when injected with 5-hydroxytryptophan (5-HTP, 100 mg/kg) 15 min after the injection of carbidopa (25 mg/kg). This was significantly decreased by pretreatment with the 5-HT1A receptor antagonist 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)-piperazine (NAN-190 5 mg/kg, 30 min prior to administration of carbidopa). Taken together, this evidence is compatible with a specific corticosterone induced facilitation of 5-HT release due to attenuation of inhibitory 5-HT1A autoreceptor function.
 ...
PMID:Effects of glucocorticoids on 5-HT1A presynaptic function in the mouse. 783 29

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT1A compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT1A compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT1A receptor.
 ...
PMID:Buspirone, gepirone, ipsapirone, and zalospirone have distinct effects on the differential-reinforcement-of-low-rate 72-s schedule when compared with 5-HTP and diazepam. 784 6

Previous studies with direct-acting serotonin (5-HT) agonists and antagonists have demonstrated that stimulation of 5-HT1A, 5-HT1C and 5-HT2 receptors may promote cortisol and prolactin (PRL) secretion in man. There is also evidence that 5-HT1C/2 receptor stimulation contributes to the cortisol and PRL responses following administration of the 5-HT precursor, L-5-hydroxytryptophan (L-5-HTP), in man. To clarify the possible contribution of 5-HT1A receptor stimulation to the ability of L-5-HTP to stimulate cortisol and PRL secretion in man, the effect of pindolol, a beta adrenoceptor antagonist that is also a 5-HT1A partial agonist, on the L-5-HTP-induced increases in cortisol and PRL secretion, was examined in 12 normal male volunteers. Pretreatment with pindolol, 30 mg orally, significantly inhibited the PRL but not the cortisol response to L-5-HTP, 200 mg PO. Pindolol alone decreased basal plasma PRL levels and increased basal plasma cortisol levels, possibly due to 5-HT1A antagonist and agonists effects, respectively. These data, coupled with observations from other studies, suggest that the L-5-HTP-induced increase in PRL but not cortisol secretion requires 5-HT1A receptor activation. PRL secretion due to 5-HT formed from exogenous L-5-HTP may require the availability of both intact 5-HT1A and 5-HT2/5-HT1C receptors, since blockade of either receptor type inhibited the PRL response to L-5-HTP. The implication of this synergistic effect for interpretation of neuroendocrine studies involving the serotonergic system in man is discussed.
 ...
PMID:Effect of pindolol on the L-5-HTP-induced increase in plasma prolactin and cortisol concentrations in man. 785 26

The purpose of the present study was to characterize U-92016A [(+)-R)-2-cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e] indole] as a 5-hydroxytryptamine (5-HT)1A receptor agonist and to compare its activity with that of standard 5-HT1A receptor agonists. U-92016A binds with high affinity to human 5-HT1A receptors expressed in Chinese hamster ovary cells (Ki = 0.2 nM). Radioligand binding studies also indicate that U-92016A is selective for the 5-HT1A receptor over other biogenic amine receptors. In Chinese hamster ovary cells expressing the human 5HT1A receptor, U-92016A decreased the forskolin-induced increase in cyclic AMP synthesis and had an intrinsic activity of 0.82 relative to 5-HT. U-92016A potently decreased rectal temperature in mice. The maximum temperature decrease was significantly greater than that observed for 8-hydroxy-di-n-propyl aminotetralin, buspirone, gepirone, ipsapirone or flesinoxan. U-92016A also elicited the 5-HT-mediated syndrome in rats and resulted in a dose-related decrease in 5-hydroxytryptophan accumulation. The compound also decreased arterial blood pressure in spontaneously hypertensive rats and inhibited sympathetic nerve activity in cats. In these assays U-92016A displayed excellent potency and a long duration of action. U-92016A also inhibited the firing of dorsal raphe 5-HT neurons and was active in two social interaction assays. The p.o. bioavailability of U-92016A was calculated to be 45%. Taken together, these data indicate that U-92016A is a metabolically stable, p.o. active 5-HT1A receptor agonist with an exceptionally high degree of intrinsic activity.
 ...
PMID:Characterization of U-92016A as a selective, orally active, high intrinsic activity 5-hydroxytryptamine1A agonist. 796 8

An abnormality of serotonergic neurotransmission has been hypothesized in p,p'-DDT intoxication to explain myoclonus and the antimyoclonic properties of 5-hydroxytryptophan (5-HTP). To study the role of serotonin (5-HT) receptors in myoclonus induced by p,p'-DDT in the rat, we performed time-course and dose-response studies of the effects of p,p'-DDT on behavior and regional 5-HT1 and 5-HT2 binding sites. At a time when low dose (80 mg/kg) p,p'-DDT elicited stimulus-sensitive and spontaneous myoclonus, there were no significant changes in Bmax or Kd of 5-HT1A, 5-HT1B, 5-HT1C sites in cortex, striatum, brainstem or spinal cord, agonist- or antagonist-labelled 5-HT2 sites in cortex, or 5-HT uptake sites. High dose p,p'-DDT (1000 but not 500 mg/kg), which also induced convulsions, only slightly increased 5-HT1 (unsubtyped) binding sites in cortex but not in brainstem or spinal cord and had no effect on antagonist-labelled 5-HT2 sites. In naive frontal cortex in vitro, 1 microM p,p'-DDT displaced neither [3H]5-HT or [3H]ketanserin specific binding. Lesions of central indoleamine neurons made with 5,7-dihydroxytryptamine significantly prolonged the latency and attenuated the severity of p,p'-DDT behavioral abnormalities, increasing the dose of p,p'-DDT which induced myoclonus (MD50) or convulsions (CD50) in 50 percent of the rats. This is the first report of 5,7-DHT-induced attenuation in the p,p'-DDT myoclonic model.
 ...
PMID:p,p'-DDT myoclonic/epileptic model: serotonin receptor binding and behavioral studies in the rat. 799 Dec 14

We studied the effects of buspirone, a 5-HT1A receptor agonist, on head twitch behavior induced by 5-hydroxy-L-tryptophan (5-HTP) administered together with pargyline in mice. Buspirone dose dependently (0.1-10 mg/kg i.p.) enhanced head twitch behavior. This effect was blocked by (-)-propranolol and NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine hydrobromide). The enhancing effect of buspirone was also observed when mice were pretreated with p-chlorophenylalanine. These findings suggest that the enhancing effect of buspirone on head twitch behavior may be exerted through the activation of post-synaptic 5-HT1A receptors.
 ...
PMID:Buspirone enhances head twitch behavior in mice. 820 Apr 25


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>