Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT1A receptor agonists: aryl-{[4-(6 -R-pyridin-2-ylmethyl)-amino]methyl}- piperidin-1-yl-methanone. Incorporati on of a fluorine atom in the beta-position to the amino function in the sid e chain led to analogues that exhibited, in general, enhanced and longlasti ng 5-HT1A agonist activity in rats after oral administration. Location of t he fluorine atom at the C-4 position of the piperidine ring was the most fa vorable, and among the various substituents tested, the ability of the fluo rine was unique in improving the oral activity of this family of ligands. T hus, the derivatives 39, 46, and 61 bound with higher affinity and selectiv ity to 6-HT1A receptors (versus dopaminergic D-2 and adrenergic alpha(1) re ceptors) and displayed more potent 5-HT1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship betwee n the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl -(4-fluoro-4([(5-(H or CH3)-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidi n-1-yl-methanone derivatives and found that the combination of a 5-methyl a nd a 6-methylamino substituent on the pyridine ring synergistically affecte d their 5-HT1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-flu oro-4{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin -1-yl-methanone 40 behaved as a more potent 5-HT1A receptor agonist in vitr o and in vivo than its 5-unsubstituted analogue 38. The antidepressant pote ntial of the lead compounds 40, 45, and 54 was examined by means of the for ced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipr amine. Thus, 40, 45, and 54 are potent, orally active 5-HT1A receptor agoni sts with marked antidepressant potential.