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 new potential antihypertensive drug, EMD 45609 (carmoxirole), has been characterized in various in vivo and in vitro models. EMD 45609 displayed high affinity for dopamine D2-receptors combined with negligible binding to D1-receptors in binding assays in vitro. However, in tests in vivo for central D2-receptor activity, EMD 45609 exhibited only weak activity. Thus, after p.o. administration, striatal L-DOPA accumulation in intact rats was unchanged up to 100 mg/kg p.o., i.e. doses 100 times higher than those reported to induce depressor activity. Central dopamine agonistic activity could only be verified in the more sensitive model of the reserpinized rat. EMD 45609 was more than 30 times less potent, however, than LY 141865 in reserpinized rats after s.c. administration. Similarly, in rats with 6-hydroxydopamine induced unilateral lesions of the substantia nigra, EMD 45609 was only marginally active. The shallow dose response curves and the submaximal effects obtained for central dopaminergic activity, as reflected in the inhibition of striatal L-DOPA accumulation, suggest that EMD 45609 is a partial dopamine D2-receptor agonist and in addition, owing to its ionizable structure, passes less readily into the brain than several reference compounds. A marked affinity was found towards 5-HT1A-receptors in vitro, whereas affinity for alpha 1- and alpha 2-adrenoceptors was low; accordingly, central alpha 2-adrenoceptor activity was not detected as EMD 45609 failed to affect hypothalamic L-DOPA accumulation even at 100 mg/kg s.c. In accordance with its high affinity for D2-receptors in vitro, EMD 45609 inhibited field stimulated noradrenaline release from rabbit ear arteries in nanomolar threshold concentrations at 0.5 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurochemical profile of EMD 45609 (carmoxirole), a dopamine DA2-receptor agonist. 168 17

EMD 49,980 proved to be a potent and selectively presynaptic D-2 dopamine receptor agonist in biochemical studies with rats. Thus, the gamma-butyrolactone-induced accumulation of dihydroxyphenylalanine, used as a presynaptic model, was antagonized with ED50 values of 0.29 and 0.09 mumol/kg in striatum and t. olfactorium, respectively, with high maximal effects. In contrast, striatal acetylcholine concentrations, reflecting actions at normosensitive postsynaptic D-2 receptors, were only moderately increased by about 30% over a dose range of 2.3-68 mumol/kg. In rats with unilateral nigrostriatal lesions, EMD 49,980 induced long-lasting contralateral turning, indicative of agonistic actions at denervated postsynaptic D-2 receptors. In addition, EMD 49,980 potently inhibited serotonin (5-HT) uptake in vitro and in vivo. Binding studies confirmed D-2 activity in the nM range but, similarly potent effects were observed at 5-HT1A binding sites. Measurement of 5-hydroxytryptophan (5-HTP) accumulation in the n. raphe revealed that, in vivo, the net effect of EMD 49,980 on 5-HT systems is an agonistic one. Control experiments indicate that inhibition of 5-HTP accumulation by EMD 49,980 is induced mainly via direct activation of 5-HT1A receptors, although some contribution due to 5-HT uptake inhibition is likely. Furthermore, results with various reference compounds make it unlikely that there are indirect effects, also via alpha 2-receptors in the models used and support the view that D-2 agonistic, 5-HT uptake inhibiting and 5-HT1A agonistic actions are independent properties of EMD 49,980.
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PMID:Biochemical and functional studies on EMD 49,980: a potent, selectively presynaptic D-2 dopamine agonist with actions on serotonin systems. 256 17

The 5-HT1A receptor agonist 8-hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT; 0.55 mg/kg s.c.) and the 5-HT (5-hydroxytryptamine, serotonin) reuptake inhibitor/5-HT1A receptor ligand 5-[4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl]-benzofuran-2-carbox ami de (EMD 68843; 55 mg/kg p.o.) inhibited ultrasonic vocalization in rats, an effect which was antagonized by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridyl)- cyclohexancarboxamide (WAY 100635; 1.0 mg/kg s.c.). 8-OH-DPAT decreased body temperature in rats, an effect which was also antagonized by WAY 100635, whereas EMD 68843 neither affected body temperature by itself nor interacted with 8-OH-DPAT or WAY 100635. The selective 5-HT reuptake inhibitor fluoxetine (100 mg/kg p.o.) had no effect on ultrasonic vocalization or body temperature. Therefore EMD 68843 is suggested to be a 5-HT1A receptor agonist selective for presynaptic 5-HT1A receptors.
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PMID:EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. 909 81

Roxindole (ROX) (EMD 49980, 5-hydroxy-3-[4-(4-phenyl-1, 2,3,6-tetrahydropyridyl(1))-butyl(1)]-indole, mesylate), a potent selective agonist of presynaptic dopamine receptors with clinical antipsychotic and antidepressant activity, was studied pharmacologically in rats (male Wistar) and mice (male Albino Swiss) with respect to its influence on the central 5-hydroxytryptamine (5-HT) system. ROX did not induce the 5-HT1A syndrome (flat body and forepaw treading) in rats, but partly antagonized the syndrome evoked by 8-OH-DPAT. The 8-OH-DPAT-induced hypothermia in mice (a 5-HT1A effect) was not inhibited by ROX. The drug evoked hypothermia, which was antagonized by pindolol, but not by (+)-WAY-100135. ROX did not inhibit the m-chlorophenylpiperazine-induced hypothermia in mice (a 5-HT1B effect), or the exploratory hypoactivity in rats (a 5-HT1C effect). Head twitches induced by a low dose of L-5-HTP were potentiated by ROX, whereas those induced by its higher dose were antagonized. ROX also antagonized the hyperthermia induced by fenfluramine or trifluoromethylphenylpiperazine at a high ambient temperature in rats (a 5-HT2A effect). The results obtained indicate that ROX inhibits 5-HT uptake and shows 5-HT2A antagonistic and probably a 5-HT1B agonistic activities.
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PMID:Roxindole, a dopamine autoreceptor agonist with a potential antidepressant activity. II. Effects on the 5-hydroxytryptamine system. 913 25

The behavioral and biochemical effects of EMD 57445, a selective sigma receptor ligand with potential antipsychotic activity, on the 5-hydroxytryptamine (5-HT) system were studied in rats and mice. The drug influence was investigated in three behavioral tests: 8-OH-DPAT (5-HT1A agonist)-induced behavioral syndrome in rats, m-chlorophenylpiperazine (m-CPP, 5-HT1B agonist)-induced hypothermia in mice and L-5-hydroxytryptophan (L-5-HTP)-induced head twitches (5-HT2A stimulation) in rats. EMD 57445 did not show any activity in all three behavioral models. In biochemical studies, no changes in the 5-HT and 5-HIAA levels in rat brain cortex, nucleus accumbens, striatum, hypothalamus and hippocampus were found. The results indicate that EMD 57445 does not interact with 5-HT (5-HT1A, 5-HT1B, 5-HT2A) receptor subpopulations and does not affect 5-HT metabolism.
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PMID:EMD 57445, the selective sigma receptor ligand, has no effect on the 5-hydroxytryptamine system. 956 54

The use of so-called, atypical antipsychotic medication is becoming more widespread in the treatment of psychotic disorders. EMD 128 130 is a novel compound acting as an agonist at the 5-HT1A receptor, and as an antagonist at the dopamine-2 (D2) receptor. This dual action may confer additional benefits over selective D2 antagonists in the treatment of psychotic disorders. In this study, we investigated the occupancy of EMD 128 130 in vivo at the human D2 and 5-HT1A receptors with positron emission tomography using the radiotracers [11C]raclopride and [11C]WAY-100635. Seven healthy volunteers were examined before and after 5 days of treatment with EMD 128 130, administered in an incremental dose building up to 50 mg, b.d. A significant occupancy was demonstrated at the human D2 receptor (40% following a dose of 50 mg, b.d.) while there was no consistent effect observed at the 5-HT1A receptor, despite a similar affinity of EMD 128 130 for cloned human D2 and 5-HT1A receptors, and the presence of typical, central 5-HT1A agonist side-effects. The differential effects of EMD 128 130 at the D2 and the 5-HT1A receptor (antagonist at D2 receptor, agonist at the 5-HTIA receptor) may explain the differences in occupancy observed.
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PMID:Evaluation of EMD 128 130 occupancy of the 5-HT1A and the D2 receptor: a human PET study with [11C]WAY-100635 and [11C]raclopride. 1223 24

We examined the effect of Vilazodone, a selective serotonin reuptake inhibitor (SSRI) and serotonin 1A (5-HT(1A)) receptor agonist [Bartoszyk, G.D., Hegenbart, R., Ziegler, H., 1997. EMD 68843, a serotonin reuptake inhibitor with selective presynaptic 5-HT1A receptor agonistic properties. Eur. J. Pharmacol. 322, 147-153.], on change in affect following predator stress. Vilazodone and vehicle injection (intraperitoneal) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing). Predator stress involved unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus-maze, and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus-maze and elevated response to acoustic startle. In prophylactic testing, Vilazodone affected stress potentiation of startle at doses above 5 mg/kg. Vilazodone increased stress elevation of startle at 10 mg/kg. Higher doses of Vilazodone (20 and 40 mg/kg) blocked stress potentiation of startle. In contrast, Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. In therapeutic testing, Vilazodone increased stress elevation of startle at all doses. In contrast, therapeutic Vilazodone had no effect on stress potentiation of anxiety in the plus-maze. Taken together, the data suggest a prophylactic potential for Vilazodone in the treatment of changes in hypervigilance following severe stress.
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PMID:Effects of systemic injections of vilazodone, a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist, on anxiety induced by predator stress in rats. 1550 23

Vilazodone (EMD 68843; 5-{4-[4-(5-cyano-3-indolyl)-butyl]-1-piperazinyl}-benzofuran-2-carboxamide hydrochloride) is a combined serotonin specific reuptake inhibitor (SSRI) and 5-HT1A receptor partial agonist currently under clinical evaluation for the treatment of major depression. This molecule was designed based on the premise that negative feedback circuitry, mediated via 5-HT1 receptors, limits the acute SSRI-induced enhancements in serotonergic neurotransmission. If the hypothesis is correct, combination of SSRI with 5-HT1A partial agonism should temporally enhance the neuroplastic adaptation and subsequently hasten therapeutic efficacy compared to current treatments. Preclinical in vitro evaluation has confirmed vilazodone's primary pharmacological profile both in clonal and native systems, that is, serotonin reuptake blockade and 5-HT1A partial agonism. However, in vivo and in contrast to combination of 8-OH-DPAT and paroxetine, vilazodone selectively enhanced serotonergic output in the prefrontal cortex of rats. Behavioral evaluations, in the ultrasonic vocalization model of anxiety in rats, demonstrated anxiolytic efficacy. In the forced swim test (a putative model of depression), vilazodone also showed efficacy but at a single dose only. In man, vilazodone abolished REM sleep and demonstrated clinical antidepressant efficacy equivalent to an SSRI. Ongoing clinical evaluations will hopefully reveal whether the founding hypothesis was valid and if vilazodone will produce a more rapid onset of antidepressant efficacy.
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PMID:Vilazodone: a 5-HT1A receptor agonist/serotonin transporter inhibitor for the treatment of affective disorders. 1949 24