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 ability of 5-HT1A and 5-HT1B agonists to alter a spinal animal's nociceptive threshold was examined using two analgesiometric tests. In the spinal withdrawal reflex test, administration of the selective 5-HT1A agonists ipsapirone, gepirone and PAPP resulted in significant dose-dependent increases in receptive field (RF) area for withdrawal reflexes when compared to predrug baseline values, indicating an increase in nociceptive sensitivity. The average overall percent maximal increase in RF area following administration of 5-HT1A selective compounds was: 80 +/- 16% for the ventroflexion reflex, 90 +/- 6% for the dorsiflexion reflex and 87 +/- 8% for the lateral flexion reflex. Similar to the effects noted with 5-HT1A agonists, administration of 5-HT1B agonists RU24969, mCPP and TFMPP resulted in a hyperalgesic response with an overall percent maximal increase of 43 +/- 6% for the ventroflexion reflex, 51 +/- 6% for the dorsiflexion reflex and 38 +/- 9% for the lateral flexion reflex. In the tail-flick analgesiometric test, administration of the 5-HT1A agonists 8-OH-DPAT and ipsapirone and the 5-HT1B agonists RU24969 and mCPP resulted in a significant dose-dependent increase in tail-flick latencies when compared to predrug baseline values, indicating a decrease in nociceptive sensitivity to noxious thermal stimuli. No differences in magnitude of the effect of the two receptor subtypes were found, indicating that stimulation of either 5-HT1A or 5-HT1B receptors was equipotent in producing the antinociceptive tail-flick response.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Role of spinal serotonin1 receptor subtypes in thermally and mechanically elicited nociceptive reflexes. 141 Jan 32

The serotonin (5-HT)1A agonist, LY 165,163 (1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine) , also known as PAPP, has been suggested to exert effects via an interaction with dopamine receptors. Thus, in this study, we examined its ability to induce rotation in rats sustaining unilateral 6-hydroxy-dopamine lesions of the substantia nigra, an in vivo model of dopaminergic activity. In analogy to the direct dopamine (mixed D1/D2) agonist, apomorphine, (0.01-0.63 mg/kg), LY 165,163 (0.16-10.0 mg/kg) dose-dependently elicited robust and sustained contralateral rotation. Its maximal effect was comparable to that of apomorphine and its duration of action more extended. Rotation elicited by LY 165,163 (10.0 mg/kg) was resistant to the 5-HT1A antagonist, (-)-alprenolol. It was also unaffected by the selective D1 antagonist, SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5,tetrahydro-1H-3-be nza zepine) (2.5 mg/kg) or the selective D2 antagonist, raclopride (10.0 mg/kg) when each was administered alone. However, upon joint administration they clearly diminished the effect of LY 165,163. The dopamine antagonist, haloperidol (D2 greater than D1) also reduced the action of LY 165,163. This profile of partial antagonism by mixed D1 and D2 receptor blockade has been reported previously for apomorphine and contrasts to that seen with selective D1 or D2 agonists, the actions of which are completely blocked by D1 or D2 antagonists, respectively. In conclusion, the present data demonstrate that LY 165,163 exerts pronounced rotation in nigral-lesioned rats: this reflects a mixed D1/D2 action rather than an activation of 5-HT1A sites.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The serotonin (5-HT)1A agonist, LY 165,163, induces contralateral rotation in unilateral substantia nigra-lesioned rats via dopamine receptors. 179 76

The present study was conducted to investigate the effects of various 5-hydroxytryptamine (5-HT) agonists and antagonists on motor behaviour in rats and marmosets. Various motor-based responses were assessed after central or peripheral administration of 5-HT agents to rats and marmosets. Drugs acting as agonists at the 5-HT1A receptor (8-OHDPAT, gepirone, BMY-7378, NAN-190, PAPP (LY165163) and flesinoxan) and 5-HT2/1C receptors (DOI) were found to reverse neuroleptic-induced catalepsy in the rat whereas 5-HT2/1C antagonists (mianserin, ritanserin and ICI-170,809) and the 5-HT1 antagonist ((+/-)pindolol) increased catalepsy. Agonists acting at 5-HT3 receptors (phenylbiguanide and 2-methyl-5-HT) had no effect on catalepsy. The putative 5-HT1A antagonist, (+/-) pindolol, attenuated the reversal of catalepsy by 8-OHDPAT. Although both 8-OHDPAT and BMY-7378 were tested, only the latter was found to reduce apomorphine-induced stereotypy. Bilateral or unilateral infusions of 8-OHDPAT, BMY-7378 or pindolol into the substantia nigra of non-lesioned rats had no effect on spontaneous locomotor or rotational activity, respectively. However, 8-OHDPAT and BMY-7378 were found to increase or decrease motor activity, after injection into the median or dorsal raphe nuclei, respectively. Finally, 8-OHDPAT and BMY-7378 were found to be inactive against MPTP-induced bradykinesia in the marmoset. It is concluded that both 5-HT1A and 5-HT2/1C receptors are involved in the anti-cataleptic effects of 5-HT agents. The 5-HT1A receptors are probably situated within the raphe, whereas the location of the 5-HT2/1C receptors remains undetermined.
 ...
PMID:Behavioural effects of serotonin agonists and antagonists in the rat and marmoset. 212 71

5-Hydroxytryptamine (serotonin, 5-HT) stimulates basal adenylyl cyclase activity in membranes from guinea pig or rat hippocampi, but 5-HT inhibits forskolin-stimulated adenylyl cyclase activity in these same membranes. The opposing effects of 5-HT on adenylyl cyclase activity indicate that distinct 5-HT receptors, positively and negatively coupled to adenylyl cyclase, are present in these membranes. Stimulation of adenylyl cyclase activity is mediated by two distinct 5-HT receptors. The receptor with lower affinity for 5-HT, designated as RL, is apparently homologous with a 5-HT receptor present in rat collicular membranes, but it is not homologous with the stimulatory receptor characterized in neuroblastoma hybrid cell (NCB-20) membranes. The receptor with higher affinity for 5-HT is homologous with the 5-HT1A binding site. The magnitude of stimulation by 5-HT1A receptors is variable with respect to stimulation by RL and is sometimes completely absent. Inhibition of forskolin-stimulated adenylyl cyclase activity, in membranes from either rat or guinea pig hippocampus or rat cortex, is a functional correlate of the 5-HT1A binding site. This inhibitory response was used to determine the pharmacological characteristics of drugs that reportedly have high affinity for 5-HT1A binding sites, such as 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) and (-)pindolol. PAPP inhibited adenylyl cyclase activity in guinea pig hippocampal membranes with an EC50 value of 27 +/- 3 nM. (-)Pindolol was a partial agonist in inhibiting adenylyl cyclase activity in guinea pig and rat hippocampal membranes. Because of the low intrinsic activity of (-)pindolol, it was tested as an antagonist of the inhibition produced by 5-HT1A receptor agonists in rat hippocampal membranes. The Kb of (-)pindolol was 40 nM as measured by a Schild plot. (-)Propranolol was a simple competitive antagonist at the rat hippocampal receptor with a Kb value of 550 nM. In summary, guinea pig and rat hippocampal membranes possess two distinct populations of 5-HT receptors, a 5-HT receptor that mediates inhibition of adenylyl cyclase activity and is pharmacologically homologous with the 5-HT1A binding site, and a stimulatory receptor that appears to be homologous with the 5-HT receptor first characterized in infant rat collicular membranes.
 ...
PMID:Stimulation and inhibition of adenylyl cyclase by distinct 5-hydroxytryptamine receptors. 222 10

In studying the role of serotonin (5-HT) in the mechanism of action of benzodiazepine (BDZ)-induced wet-dog shakes (WDS), only certain 1,4-substituted BDZ agonists were found to induce WDS at doses up to 60 mg/kg in the rat with the rank order of potency at peak dose effect clonazepam greater than nitrazepam = flunitrazepam much greater than nimetazepam = lorazepam. BDZs evoking WDS at lowest doses contained an R7 nitro group on the A ring. Non-BDZ agonists (CL 218,872), inverse agonists (beta-CCE), peripheral type receptor agonists (Ro 5-4864), and BDZ antagonists (Ro 15-1788) did not induce shaking behavior. Several 5-HT1 and 5-HT2 agonists and antagonists were tested as blockers, but only putative 5-HT1A agonists reduced WDS, 8-OH-DPAT and ipsapirone but not PAPP and 5-MeO-DMT having a significant effect. The effect of 8-OH-DPAT was dose dependent, with an ID50 of 0.86 mg/kg, but it was not reversed by 5-HT or adrenergic antagonists at the doses studied. Intracisternal 5,7-dihydroxytryptamine lesions did not alter frequency, latency, or time course of BDZ-induced WDS. BDZ-evoked WDS were enhanced by Ro 15-1788 (which inhibited ataxia) but were unaffected by the various types of BDZ agonists. Several BDZ agonists induced both WDS and ataxia, but ataxia was not blocked by serotonergic drugs. No significant correlation with ataxia, BDZ radioligand binding, antipentylenetetrazol activity, or other BDZ property was found. BDZ-evoked WDS may relate to the unique predominance of BDZ II and 5-HT1A receptors in the hippocampus, an important site for WDS, but 5-HT1A agonists appear to modulate WDS by opposing pharmacologic actions rather than by direct receptor antagonism. These data indicate a species difference in the shakes induced by BDZs in rats (5-HT2 independent) and in mice (5-HT2 related).
 ...
PMID:Benzodiazepine-induced shaking behavior in the rat: structure-activity and relation to serotonin and benzodiazepine receptors. 254 77

The effects of several putative 5-HT1 receptor-subtype selective ligands were investigated in biochemical 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 phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(m-trifluoromethylphenyl)piperazine), mCPP (1-(m-chlorophenyl)piperazine), CGS 12066 (7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)- piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5-HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HT1B versus 5-HT1A selective. Quipazine showed equal potency at 5-HT1B and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? 277 Aug 89

1. The abilities of two indole agonists and some nonindole agonists to induce relaxation of catch contraction and the influence of the agonists on cyclic AMP (cAMP) levels in the anterior byssus retractor muscle (ABRM) of Mytilus were investigated. 2. 5-MeOT (5-methoxytryptamine) and 5-MeODMT (5-methoxy-N,N-dimethyltryptamine) dose-dependently relaxed the contraction. 3. TFMPP (m-trifluoromethylphenyl piperazine), PAPP (p-amino-phenyl TFMPP) and mCPP (1-(3-chlorophenyl)piperazine dose-dependently relaxed the contraction, but 2MPP (1-(2-methylphenyl) piperazine and quipazine did not. 4. 5-MeOT (10(-6)M), 5-MeODMT (10(-6)M), TFMPP (10(-4)M), 2MPP (10(-4)M), quipazine (10(-4)M) and 8-OH-DPAT (3 x 10(-5) M) significantly reduced the cAMP levels, but PAPP (3 x 10(-4)M) and mCPP (10(-4)M) did not have any effect on cAMP levels. 5. These findings indicate that the pharmacological properties of 5-HT1-like receptors in the ABRM are similar to those of 5-HT1A receptors in mammalian tissues, and that the changes in cAMP levels induced by the agonists used are unlikely to be directly linked to the relaxation induced by them.
 ...
PMID:The relaxation induced by indole and nonindole 5-HT agonists in the molluscan smooth muscle. 290 67

1-[2-(4-Aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (PAPP) inhibits [3H]5-hydroxytryptamine (5-HT, serotonin) binding to 5-HT1A and 5-HT1B sites in rat brain with apparent equilibrium dissociation constants (KD) of 2.9 and 328 nM, respectively. [3H]PAPP was synthesized, its binding to central serotonin receptors was examined, and its potential usefulness as a 5-HT1A receptor radioligand was evaluated. With either 10 microM 5-HT or 1 microM 8-hydroxy-2-(di-n-propylamino)tetralin to define nonspecific binding, [3H]PAPP bound to a single class of sites in rat cortical membranes with a KD of 1.6 nM and a maximal binding density (Bmax) of 162 fmol/mg of protein. d-Lysergic acid diethylamide and 5-HT, two nonselective inhibitors of [3H]5-HT binding, displaced 1 nM [3H]PAPP with a potency that matched their affinity for 5-HT1 receptors. Spiperone and 8-hydroxy-2-(di-n-propylamino)tetralin, two compounds that discriminate [3H]5-HT binding to 5-HT1A and 5-HT1B sites, inhibited [3H]PAPP binding in accordance with their much higher affinities for the 5-HT1A receptor subtype. Furthermore, the ability of N-(m-trifluoromethylphenyl)piperazine and ketanserin to inhibit [3H]PAPP binding reflected their low affinities for the 5-HT1A receptor. Several nonserotonergic compounds were also found to be relatively poor displacers of [3H]PAPP binding. The regional distribution of serotonin-sensitive [3H]PAPP sites correlated with the densities of 5-HT1A receptors in the cortex, hippocampus, corpus striatum, and cerebellum of the rat. These results indicate that [3H]PAPP binds selectively and with high affinity to 5-HT1A receptor sites in rat brain.
 ...
PMID:[3H]1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine: a selective radioligand for 5-HT1A receptors in rat brain. 293 90

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.
 ...
PMID:Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163. 295 21

The putative 5-HT1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY165163, PAPP) (1, 2, 4, 10 mg/kg s.c.) caused a significant and dose-dependent hypothermia in rats, 30 and 60 min after injection. The decreases of temperature were less marked than that caused by 8-OH-DPAT 1 mg/kg s.c.). Depletion of brain serotonin (5-HT) by 91% following pretreatment with p-chlorophenylalanine (pCPA) (150 mg/kg i.p. on three successive days) significantly enhanced the hypothermic effects of both 8-OH-DPAT (0.25 mg/kg s.c.) and LY165163 (4 mg/kg s.c.). LY165163-induced hypothermia was also somewhat enhanced following depletion of hypothalamic 5-HT by 76% after infusion of 5,7-dihydroxytryptamine (5,7-DHT) (150 micrograms) into the third ventricle. Results indicate that the hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT in the rat is not dependent on presynaptic 5-HT stores and is therefore probably mediated by postsynaptic 5-HT receptors.
 ...
PMID:Hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT is not prevented by 5-HT depletion. 296 83


1 2 Next >>