ChemInform Abstract: Design and Synthesis of a Series of 6-Substituted-2-pyridinylmethylamine Derivatives as Novel, High-Affinity, Selective Agonists at 5-HT1A Receptors

A search for novel, selective agonists with high intrinsic activity at the 5-HT1A subtype of serotonin (5-HT) receptors was undertaken. Mechanistic and thermodynamic considerations led to the design of 6-substituted-2-pyridinylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, α1-adrenergic, and D2-dopaminergic receptors. Compounds with high affinity for 5-HT1A receptors (pKi ≥ 8) were examined for agonist properties by measuring their ability to inhibit forskolin-stimulated cAMP production in HA7 cells (i.e., HeLa cells permanently transfected with the h5-HT1A receptor gene and expressing the h5-HT1A receptor protein). Several compounds of the type aryl{4-[(6-substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective with respect to α1 and D2 sites. Importantly, their 5-HT1A agonist properties we...