Design and synthesis of a series of 6-substituted-2- pyridinylmethylamine derivatives as novel, high-affinity, selective agonists at 5-HT(1A) receptors

Bernard Vacher, Bernard Bonnaud, Philippe Funes, Nathalie Jubault, Wouter Koek, Marie Bernadette Assié, Cristina Cosi

Research output: Contribution to journalArticle

32 Scopus citations


A search for novel, selective agonists with high intrinsic activity at the 5-HT(1A) 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-HT(1A) pharmacophore. Various adducts derived from the 6-substituted-2-pyridinylmethylamine moiety were tested for their affinity at 5-HT(1A), α1-adrenergic, and D2- dopaminergic receptors. Compounds with high affinity for 5-HT(1A) receptors (pK(i) ≥ 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-HT(1A) receptor gene and expressing the h5-HT(1A) receptor protein). Several compounds of the type aryl{4-[(6- substituted-pyridin-2-ylmethylamino)methyl]piperidin-1-yl}methanone had nanomolar affinity for 5-HT(1A) binding sites and were more than 500-fold selective with respect to α1 and D2 sites. Importantly, their 5-HT(1A) agonist properties were demonstrated in HA7 cells where they behaved as potent inhibitors of cAMP accumulation. In particular, (3,4- dichlorophenyl){4-[(6-oxazol-5-ylpyridin-2-ylmethylamino)methyl]piperidin- 1-yl}methanone (70) and (3,4-dichlorophenyl){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-HT(1A) agonist (±)-8-OH-DPAT. SAR studies revealed that the pyridine nitrogen atom and the nature and the position of the substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT(1A) receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT(1A) binding sites.

Original languageEnglish (US)
Pages (from-to)5070-5083
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number25
StatePublished - Dec 3 1998


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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