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1.
Psychopharmacology (Berl) ; 155(4): 426-33, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11441433

ABSTRACT

RATIONALE: Urotensin-II (U-II) has recently been identified as an agonist for the G-protein-coupled receptor, GPR14. Detection of both U-II and GPR14 mRNA in the brain and spinal cord is consistent with a role for U-II in the CNS. However, the effects of central administration of U-II in rodents have not been reported previously. OBJECTIVES: To determine the localisation of GPR14 mRNA in rat tissues and to investigate the behavioural and endocrine effects of human U-II (hU-II) following intracerebroventricular (ICV) administration in rats. METHODS: Experiments were carried out in male Sprague-Dawley rats. Expression of GPR14 mRNA in rat brain was determined by semi-quantitative RT-PCR. Effects of hU-II on general behaviours were assessed by an observer and the motor activity response was measured by an automated activity monitor. Plasma hormones and [DOPAC + HVA]/[DA] and [5-HIAA]/[5-HT] ratios in five brain areas were measured 20 min post-hU-II (ICV). RESULTS: GPR14 mRNA expression was found in whole brain tissue and in all CNS regions tested. GPR14 mRNA expression was also detected in the periphery; highest levels were found in the heart. Following ICV administration, hU-II (3-10 micrograms ICV) increased rearing and grooming, and increased motor activity in a familiar environment. Further, hU-II increased plasma prolactin and TSH but did not affect levels of corticosterone. hU-II had no effects on dopamine or 5-HT levels or their metabolites in the frontal cortex, hippocampus, hypothalamus, striatum and nucleus accumbens. CONCLUSIONS: These data provide further insight into the distribution of GPR14 mRNA within the CNS and show for the first time that hU-II causes marked behavioural and endocrine effects.


Subject(s)
Behavior, Animal/drug effects , Central Nervous System/drug effects , Receptors, G-Protein-Coupled , Urotensins/pharmacology , Animals , Brain Chemistry/drug effects , Endocrine Glands/drug effects , Endocrine Glands/metabolism , In Situ Hybridization , Injections, Intraventricular , Motor Activity/drug effects , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/biosynthesis , Receptors, Cell Surface/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Urotensins/administration & dosage
2.
Bioorg Med Chem Lett ; 11(5): 685-8, 2001 Mar 12.
Article in English | MEDLINE | ID: mdl-11266169

ABSTRACT

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).


Subject(s)
Dopamine Antagonists/chemistry , Dopamine Antagonists/pharmacology , Indoles/chemistry , Indoles/pharmacology , Receptors, Dopamine D2/metabolism , Animals , Brain/metabolism , CHO Cells , Cricetinae , Dopamine Antagonists/chemical synthesis , Dopamine Antagonists/metabolism , Drug Design , Humans , Indoles/chemical synthesis , Indoles/metabolism , Models, Molecular , Molecular Structure , Radioligand Assay , Rats , Receptors, Dopamine D3
3.
Bioorg Med Chem Lett ; 10(22): 2553-5, 2000 Nov 20.
Article in English | MEDLINE | ID: mdl-11086728

ABSTRACT

Starting from the dopamine D3 receptor antagonist SB-277011 1, a series of 2,3,4,5-tetrahydro-1H-3-benzazepines has been identified with high affinity for the dopamine D3 receptor and selectivity over the D2 receptor. The 3-acetamido-2-fluorocinnamide derivative 20 gave high D3 receptor affinity (pKi 8.4) with 130-fold selectivity over the 2, receptor.


Subject(s)
Nitriles/pharmacology , Quinolines/pharmacology , Receptors, Dopamine D2/drug effects , Tetrahydroisoquinolines , Animals , Nitriles/chemistry , Quinolines/chemistry , Rats , Receptors, Dopamine D3
4.
Eur J Pharmacol ; 407(1-2): 47-51, 2000 Oct 27.
Article in English | MEDLINE | ID: mdl-11050289

ABSTRACT

The dopaminergic system has long been implicated in the mechanisms of reward and addiction. 1-(4-(2-Naphthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCl (BP 897) has been claimed to be a selective dopamine D3 receptor partial agonist and has recently been shown to inhibit cocaine-seeking behaviour, suggesting a role for dopamine D3 receptor agonists in the treatment of addiction. We have previously characterised the pharmacological profile of the human dopamine D3 and D2(long) receptors using microphysiometry and radioligand binding and we have now studied the interaction of BP 897 with the dopamine D2 and D3 receptors using these methods. At both human dopamine D3 and D2 receptors, BP 897 lacked agonist activity but was a potent and selective antagonist with pK(b) values of 8.05+/-0.16 (4) and 9.43+/-0.22 (4) at human dopamine D2 and D3 receptors, respectively. These results, therefore, suggest that it may be the dopamine D3 receptor antagonist properties of BP 897 which have potential in the treatment of addiction and withdrawal.


Subject(s)
Dopamine Agonists/pharmacology , Piperazines/pharmacology , Receptors, Dopamine D2/drug effects , Animals , Azepines/pharmacology , CHO Cells , Cricetinae , Humans , Quinpirole/pharmacology , Receptors, Dopamine D2/physiology , Receptors, Dopamine D3
6.
Bioorg Med Chem Lett ; 10(16): 1863-6, 2000 Aug 21.
Article in English | MEDLINE | ID: mdl-10969986
8.
J Pharmacol Exp Ther ; 294(3): 1154-65, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10945872

ABSTRACT

SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.


Subject(s)
Dopamine Antagonists/pharmacology , Nitriles/pharmacology , Quinolines/pharmacology , Receptors, Dopamine D2/drug effects , Tetrahydroisoquinolines , Animals , Brain/metabolism , CHO Cells , Catalepsy/chemically induced , Cricetinae , Dopamine Antagonists/metabolism , Dopamine Antagonists/toxicity , Humans , Male , Microdialysis , Motor Activity/drug effects , Nitriles/metabolism , Nitriles/toxicity , Prolactin/blood , Quinolines/metabolism , Quinolines/toxicity , Radioligand Assay , Rats , Rats, Inbred Strains , Rats, Sprague-Dawley , Receptors, Dopamine D2/metabolism , Receptors, Dopamine D3 , Reflex, Startle/drug effects , Reverse Transcriptase Polymerase Chain Reaction , Transfection
9.
J Med Chem ; 43(9): 1878-85, 2000 May 04.
Article in English | MEDLINE | ID: mdl-10794704

ABSTRACT

A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.


Subject(s)
Central Nervous System/metabolism , Dopamine Antagonists/chemical synthesis , Nitriles/chemical synthesis , Quinolines/chemical synthesis , Receptors, Dopamine D2/drug effects , Tetrahydroisoquinolines , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , CHO Cells , Catalepsy/chemically induced , Catalepsy/psychology , Central Nervous System/drug effects , Cricetinae , Dopamine Antagonists/pharmacokinetics , Dopamine Antagonists/pharmacology , Half-Life , Humans , Male , Microdialysis , Nitriles/pharmacokinetics , Nitriles/pharmacology , Prolactin/blood , Quinolines/pharmacokinetics , Quinolines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D3
10.
Br J Pharmacol ; 130(3): 539-48, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10821781

ABSTRACT

The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). Following a single dose (3 mg kg(-1)) SB-269970 was detectable in rat brain at 30 (87 nM) and 60 min (58 nM). In guinea-pigs, brain levels averaged 31 and 51 nM respectively at 30 and 60 min after dosing, although the compound was undetectable in one of the three animals tested. 5-CT (0.3 mg kg(-1) i.p.) induced hypothermia in guinea-pigs was blocked by SB-269970-A (ED(50) 2.96 mg kg(-1) i.p.) and the non-selective 5-HT(7) receptor antagonist metergoline (0.3 - 3 mg kg(-1) s.c.), suggesting a role for 5-HT(7) receptor stimulation in 5-CT induced hypothermia in guinea-pigs. SB-269970-A (30 mg kg(-1)) administered at the start of the sleep period, significantly reduced time spent in Paradoxical Sleep (PS) during the first 3 h of EEG recording in conscious rats.


Subject(s)
Phenols/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Sulfonamides/pharmacology , Adenylyl Cyclases/metabolism , Animals , Body Temperature/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Guinea Pigs , Hippocampus/metabolism , Humans , Male , Membranes/metabolism , Phenols/pharmacokinetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Serotonin Antagonists/pharmacokinetics , Sleep/drug effects , Sleep Stages/drug effects , Sulfonamides/pharmacokinetics
11.
J Med Chem ; 43(6): 1123-34, 2000 Mar 23.
Article in English | MEDLINE | ID: mdl-10737744

ABSTRACT

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5-HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.


Subject(s)
Anti-Anxiety Agents/chemical synthesis , Antidepressive Agents/chemical synthesis , Indoles/chemical synthesis , Pyridines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/chemical synthesis , Administration, Oral , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/metabolism , Anti-Anxiety Agents/pharmacology , Antidepressive Agents/chemistry , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Cell Line , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Models, Molecular , Motor Activity/drug effects , Pyridines/chemistry , Pyridines/metabolism , Pyridines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 9(18): 2715-20, 1999 Sep 20.
Article in English | MEDLINE | ID: mdl-10509922

ABSTRACT

A novel series of 5,6,7,8-tetrahydroquinazolines, 4,5,6,7-tetrahydroindazoles and 4,5,6,7-tetrahydrobenzothiazoles has been prepared, having high affinity and selectivity for the dopamine D3 receptor. The 4-methoxy-5,6,7,8-tetrahydroquinazoline 6i and 2-amino-4,5,6,7-tetrahydrobenzothiazole 8 proved to be agonists with among the highest D3 receptor affinities and selectivities reported to date.


Subject(s)
Heterocyclic Compounds/chemistry , Receptors, Dopamine D2/metabolism , Tetrahydronaphthalenes/chemistry , Heterocyclic Compounds/metabolism , Protein Binding , Receptors, Dopamine D3 , Tetrahydronaphthalenes/metabolism
15.
Bioorg Med Chem Lett ; 9(2): 179-84, 1999 Jan 18.
Article in English | MEDLINE | ID: mdl-10021923

ABSTRACT

Using clearance and brain penetration studies as a screen, tetrahydroisoquinoline 3 was identified as a lead having low clearance in rats (CLb 20 ml/min/kg). Introduction of a 7-CF3SO2O- substituent into the tetrahydroisoquinoline, followed by replacement of the biphenylamido group of 3 by a 3-indolylpropenamido group gave 31, having high D3 receptor affinity (pKi 8.4) and 150 fold selectivity over the D2 receptor.


Subject(s)
Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Receptors, Dopamine D2/chemistry , Animals , Brain/drug effects , Isoquinolines/administration & dosage , Isoquinolines/blood , Models, Molecular , Rats , Receptors, Dopamine D3
16.
Bioorg Med Chem ; 7(12): 2767-73, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10658582

ABSTRACT

A model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT2C receptor affinities and selectivities over the closely related 5-HT2A receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridylcarbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists.


Subject(s)
Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Animals , Humans , In Vitro Techniques , Kinetics , Magnetic Resonance Spectroscopy , Models, Chemical , Phenylurea Compounds/chemical synthesis , Pyridines/chemical synthesis , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Structure-Activity Relationship
17.
J Med Chem ; 41(10): 1598-612, 1998 May 07.
Article in English | MEDLINE | ID: mdl-9572885

ABSTRACT

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor model and our proposed binding mode for this class of ligands within that model.


Subject(s)
Anti-Anxiety Agents , Indoles , Models, Molecular , Pyridines , Receptors, Serotonin/drug effects , Serotonin Antagonists , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/metabolism , Anti-Anxiety Agents/pharmacology , Conditioning, Operant/drug effects , Conflict, Psychological , Indoles/chemical synthesis , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacology , Male , Motor Activity/drug effects , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/metabolism , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT2B , Receptor, Serotonin, 5-HT2C , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Serotonin Antagonists/metabolism , Serotonin Antagonists/pharmacology , Social Behavior , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 8(20): 2859-64, 1998 Oct 20.
Article in English | MEDLINE | ID: mdl-9873637

ABSTRACT

Starting from a series of 2-aminotetralins 1, a novel series of N-[4-(4-phenylbenzoylamino)butyl]-octahydrobenzoquinolines and hexahydrobenzoindoles with high potency and selectivity for the dopamine D3 receptor has been designed. The effect of ligand chirality on binding affinity has been established. Selected derivatives (e.g. 2o, 2p) show high functional selectivity and enhanced in vivo properties compared to 1.


Subject(s)
Dopamine D2 Receptor Antagonists , Tetrahydronaphthalenes/chemistry , Animals , Metabolic Clearance Rate , Rats , Receptors, Dopamine D3 , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/pharmacology
20.
Br J Pharmacol ; 125(7): 1413-20, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9884068

ABSTRACT

Xanomeline [3(3-hexyloxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-me thylpyridine] has been reported to act as a functionally selective muscarinic partial agonist with potential use in the treatment of Alzheimer's disease. This study examined the functional activity of xanomeline at 5-HT1 and 5-HT2 receptors in native tissue and/or human cloned receptors. Xanomeline had affinity for muscarinic receptors in rat cortical membranes where the ratio of the displacement affinity of [3H]-Quinuclidinyl benzilate vs that of [3H]-Oxotremorine-M was 16, indicative of partial agonist activity. Radioligand binding studies on human cloned receptors confirmed that xanomeline had substantial affinity for M1, M2, M3, M4, M5 receptors and also for 5-HT1 and 5-HT2 receptor subtypes. Carbachol and xanomeline stimulated basal [35S]-GTPgammaS binding in rat cortical membranes with micromolar affinity. The response to carbachol was attenuated by himbacine and pirenzepine with pA2 of 8.2, 6.9 respectively consistent with the response being mediated, predominantly, via M2 and M4 receptors. Xanomeline-induced stimulation of [35S]-GTPgammaS binding was inhibited by himbacine with an apparent pKb of 6.3, was not attenuated by pirenzepine up to 3 microM and was inhibited by the selective 5-HT1A antagonist WAY100635 with an apparent pKb of 9.4. These data suggest the agonist effect of xanomeline in this tissue is, in part, via 5-HT1A receptors. Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors. In studies using the fluorescent cytoplasmic Ca2+ indicator FLUO-3AM, xanomeline induced an increase in cytoplasmic Ca2+ concentration in SH-SY5Y cells expressing recombinant human 5-HT2C receptors. Atropine antagonized this response, consistent with mediation via endogenously-expressed muscarinic receptors. In the presence of atropine, xanomeline antagonized 5-HT-induced cytoplasmic changes in Ca2+ concentration in cells expressing h5-HT2A, h5-HT2B and h5-HT2c receptors with potencies similar to its affinity at these receptors. These studies indicate that xanomeline is a potent agonist at 5-HT1A and 5-HT1B receptors and an antagonist at 5-HT2 receptor subtypes.


Subject(s)
Muscarinic Agonists/pharmacology , Pyridines/pharmacology , Receptors, Serotonin/metabolism , Serotonin Receptor Agonists/pharmacology , Thiadiazoles/pharmacology , Animals , CHO Cells , Calcium/metabolism , Cells, Cultured , Cerebral Cortex/metabolism , Clone Cells , Cloning, Molecular , Cricetinae , Cytoplasm/drug effects , Cytoplasm/metabolism , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Male , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Serotonin/drug effects , Recombinant Proteins/metabolism , Serotonin Antagonists/pharmacology
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