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 an d thermodynamic considerations led to the design of 6-substituted-2-pyridin ylmethylamine as a potential 5-HT1A pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT1A, alpha(1)-adrenergic, and D-2-dopaminergic receptors. Co mpounds with high affinity for 5-HT1A receptors (pK(i) greater than or equa l to 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-substit uted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT1A binding sites and were more than 500-fold selective wit h respect to alpha(1) and D-2 sites. Importantly, their 5-HT1A agonist prop erties were demonstrated in HA7 cells where they behaved as potent inhibito rs of cAMP accumulation. In particular, (3,4-dichlorophenyl){4-[(6-oxazol-5 -ylpyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone (70) and (3,4-di chlorophenyl){4-[(6-azetidinopyridin-2-ylmethylamino)methyl]piperidin-1-yl} methanone (36) appeared to be more potent than, and at least as efficacious as, the prototypical 5-HT1A agonist (+/-)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the subs tituents on the pyridine ring were critically involved in the ability of th e compounds to recognize and activate 5-HT1A receptors. Structural modifica tions of the nonpharmacophoric part of the molecule showed, however, that t he entire structure was required for affinity at 5-HT1A binding sites.