title: In vitro characterization of AR-A000002, a novel 5-hydroxytryptamine(1B) autoreceptor antagonist.
abstract: The in vitro pharmacological properties of AR-A000002 ((R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide), a novel 5-hydroxytryptamine (5-HT)(1B) receptor antagonist, were studied. AR-A000002 bound with high affinity to guinea pig cortex and recombinant guinea pig 5-HT(1B) receptors (Ki=0.24 and 0.47 nM) and with 10-fold lower affinity to 5-HT(1D) receptors. The compound displayed weak or no affinity for 63 other binding sites tested. In [35S]GTPgammaS assays AR-A000002 showed 50% efficacy and inhibited 5-HT stimulation with 66% and a pA2 value of 8.9. In slices of guinea pig cortex, AR-A000002 enhanced the outflow of [3H]5-HT upon electrical stimulation. The compound blocked sumatriptan-evoked contraction of rabbit saphenous veins without inducing any contraction itself. Thus, in these two systems AR-A000002 behaved as a 5-HT(1B) receptor antagonist. It is concluded that AR-A000002 is a selective high affinity 5HT(1B) receptor ligand that shows partial agonist activity in recombinant systems. In native tissues AR-A000002 behaves as a 5-HT(1B) receptor antagonist.
authors.affiliation: Department of Molecular Pharmacology, Local Discovery Research Area CNS & Pain Control, Astrazeneca R&D Södertälje S-151 85, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ahlgren
authors.forename: Anders
authors.initials: A
authors.lastname: Eriksson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Tellefors
authors.forename: Svante B
authors.initials: SB
authors.lastname: Ross
authors.forename: Carina
authors.initials: C
authors.lastname: Stenfors
authors.forename: Asa
authors.initials: A
authors.lastname: Malmberg
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D044302:Receptor, Serotonin, 5-HT1B / Q000235:genetics / Q000378:metabolism; D044346:Receptor, Serotonin, 5-HT1D / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D018170:Sumatriptan / Q000494:pharmacology; D014162:Transfection; D014316:Tritium; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D017660:Autoreceptors; D001549:Benzamides; D007211:Indoles; D009025:Morpholines; C107225:N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)-3-methyl-4-(4-pyridyl)benzamide; C473209:N-(5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl)-4-morpholinobenzamide; D010881:Piperidones; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; C108518:SB 22489G; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds; D013462:Sulfur Radioisotopes; D014662:Vasoconstrictor Agents; D014316:Tritium; C101999:CP 135807; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018170:Sumatriptan