L-694,247 - A POTENT 5-HT(1D) RECEPTOR AGONIST

1 The 5-hydroxytryptamine (5-HT) receptor binding selectivity profile of a novel, potent 5-HT1D receptor agonist, L-694,247 l-1,2,4-oxadiazo l-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 a ffinity (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 respectivel y). L-694,247 retained good selectivity with respect to the 5-HT1A bin ding site (pIC50 = 8.64), the 5-HT1C binding site (6.42), the 5-HT2 bi nding site (6.50) and the 5-HT1E binding site (5.66). The pI50 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 essentia lly inactive at the 5-HT3 recognition site. 3 L-694,247, like sumatrip tan, displayed a similar efficacy to 5-HT in inhibiting forskolin-stim ulated adenylyl cyclase in guinea-pig substantia nigra although L-694, 247 (pEC50 = 9.1) was more potent than sumatriptan (6.2) in this 5-HT1 D receptor mediated functional response. L-694,247 (pEC50 = 9.4) was a lso more potent than sumatriptan (6.5) in a second 5-HT1D receptor med iated functional response, the inhibition of K+-evoked [H-3]-5-HT rele ase from guinea-pig frontal cortex slices. 4 The excellent agreement o bserved for L-694,247 between the 5-HT1D radioligand binding affinity and the functional potency confirm that the two functional models (the inhibition of forskolin-stimulated adenylyl cyclase in guinea-pig sub stantia nigra and the inhibition of K+-evoked [H-3]-5-HT release from guinea-pig frontal cortex) do indeed reflect 5-HT1D-mediated events. 5 L-694,247 is a novel, highly potent 5-HT1D/5-HT1B receptor ligand whi ch should prove useful for the exploration of the physiological role o f these receptors in animals.