Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT_1A Receptors

Abstract

The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT 1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone. Incorporation of a fluorine atom in the -position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and longlasting 5-HT 1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT 1A receptors (versus dopaminergic D 2 and adrenergic R 1 receptors) and displayed more potent 5-HT 1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between 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 CH 3 )-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT 1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT 1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced 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 imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT 1A receptor agonists with marked antidepressant potential.

Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging

“…Second, its chemical structure carries a fluorine atom amenable to radiofluoration (more convenient for clinical uses than 11 C radiolabeling). Third and importantly, F13714 exhibits an exceptionally high affinity for 5-HT 1A receptors, with a Ki of 0.1 nM or lessthat is, 0.06 nM at rat cortical 5-HT 1A receptors, 0.10 nM at rat hippocampal 5-HT 1A receptors, and 0.04 nM at recombinant human 5-HT 1A receptors expressed in Chinese hamster ovary cells (30)(31)(32). Its remarkable agonist efficacy leads some authors to consider agonists from this chemical series as superagonists (33).…”

Synthesis of a novel heterocyclic scaffold utilizing 2-cyano-N-(3-cyano-4,6-dimethyl-2-oxopyridin-1-yl) acetamide

“…2-Pyridone derivatives have appeared as vital backbones in over 7000 surviving drugs. 4,5 In particular, 2-pyridones comprising H-bond acceptor substituent in position-5 establish a relatively new class of specific phosphodiesterase 3 (PDE3) inhibitors, 6 which are used as unconventional alternatives to classic digitalis glycosides for the treatment of congestive heart failure (CHF) i.e. amrinone 7 and milrinone 8 (Fig.…”

Synthesis and Characterization of Novel (E)-1-(Aylideneamino)-6-(4-Methoxyphenyl)-2-Oxo-4-(Trifluoromethyl)-1,2-Dihydropyridine-3-Carbonitrile Derivatives

“…The pyridine ring systems have emerged as integral backbones of over 7000 existing drugs [1,2] . The pyridine ring is also an integral part of anticancer and anti-inflammatory agents [3] .…”