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The Selective 5-HT1B Receptor Inverse Agonist 1‘-Methyl-5-[[2‘-methyl-4‘- (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo
- Source :
- Journal of Medicinal Chemistry. 41:1218-1235
- Publication Year :
- 1998
- Publisher :
- American Chemical Society (ACS), 1998.
-
Abstract
- 5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.
- Subjects :
- Male
Models, Molecular
Indoles
Ketanserin
Swine
medicine.drug_class
Stereochemistry
Guinea Pigs
Ritanserin
CHO Cells
Hypothermia
In Vitro Techniques
Piperazines
Radioligand Assay
Structure-Activity Relationship
chemistry.chemical_compound
Cricetinae
Drug Discovery
medicine
Animals
Humans
Inverse agonist
Spiro Compounds
Receptor
Piperidones
Autoreceptors
Indole test
Aspartic Acid
Oxadiazoles
Receptor antagonist
Frontal Lobe
Rats
Serotonin Receptor Agonists
chemistry
Receptor, Serotonin, 5-HT1D
Receptors, Serotonin
Receptor, Serotonin, 5-HT1B
Autoreceptor
Molecular Medicine
Serotonin Antagonists
Piperidine
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....b0abdd93d86c3590513d6f50b8ec21a9