title: L-694,247: a potent 5-HT1D receptor agonist.
abstract: 1. The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 (2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl ]- 1H-indole-3-yl]ethylamine) was assessed and compared with that of the 5-HT1-like receptor agonist, sumatriptan. 2. L-694,247 had an affinity (pIC50) of 10.03 at the 5-HT1D binding site and 9.08 at the 5-HT1B binding site (sumatriptan: pIC50 values 8.22 and 5.94 respectively). L-694,247 retained good selectivity with respect to the 5-HT1A binding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 binding site (6.50) and the 5-HT1E binding site (5.66). The pIC50 values for sumatriptan at these radioligand binding sites were 6.14, 5.0, < 5.0 and 5.64 respectively. Both L-694,247 and sumatriptan were essentially inactive at the 5-HT3 recognition site. 3. L-694,247, like sumatriptan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra although L-694,247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was also more potent than sumatriptan (6.5) in a second 5-HT1D receptor mediated functional response, the inhibition of K(+)-evoked [3H]-5-HT release from guinea-pig frontal cortex slices. 4. The excellent agreement observed for L-694,247 between the 5-HTlD radioligand binding affinity and the functional potency confirm that the two functional models (the inhibition of forskolin-stimulated adenylyl cyclase in guinea-pig substantia nigra and the inhibition of K+-evoked [3H]-5-HT release from guinea-pig frontal cortex) do indeed reflect 5-HTID-mediated events.5. L-694,247 is a novel, highly potent 5-HTID/5-HTIB receptor ligand which should prove useful for the exploration of the physiological role of these receptors in animals.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex.
authors.forename: M S
authors.initials: MS
authors.lastname: Beer
authors.forename: J A
authors.initials: JA
authors.lastname: Stanton
authors.forename: Y
authors.initials: Y
authors.lastname: Bevan
authors.forename: A
authors.initials: A
authors.lastname: Heald
authors.forename: A J
authors.initials: AJ
authors.lastname: Reeve
authors.forename: L J
authors.initials: LJ
authors.lastname: Street
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
authors.forename: D N
authors.initials: DN
authors.lastname: Middlemiss
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*; D013268:Stimulation, Chemical; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D013552:Swine; D014316:Tritium; D014363:Tryptamines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010069:Oxadiazoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D014316:Tritium; C085632:L 694247; D005576:Colforsin; D012701:Serotonin; D000262:Adenylyl Cyclases; D011188:Potassium