Design and Synthesis of a Series of 6-Substituted-2-pyridinylmethylamine Derivatives as Novel, High-Affinity, Selective Agonists at 5-HT_1AReceptors

Abstract

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, alpha1-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 alpha1 and D2 sites. Importantly, their 5-HT1A 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-ylmethylamin o)methyl]pip eridin-1-yl¿methanone (70) and (3, 4-dichlorophenyl)¿4-[(6-azetidinopyridin-2-ylmethylamino)met hyl]piper idin-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 substituents on the pyridine ring were critically involved in the ability of the compounds to recognize and activate 5-HT1A receptors. Structural modifications of the nonpharmacophoric part of the molecule showed, however, that the entire structure was required for affinity at 5-HT1A binding sites.

2,6-Dichloro-3-nitropyridine

“…For the role of the nitropyridine nucleus in the development of medicinal agents and in the field of agrochemicals, see: Davis et al (1996). For the properties and use of pyridine derivatives, see: Vacher et al (1998); Olah et al (1980); Bare et al (1989). For standard bond lengths, see: Allen et al (1987).…”

“…(Davis et al, 1996). It is seen from the current literature that pyridine derivatives have been developed and used as insecticidal agents (Vacher et al, 1998). Nitrated pyridines and their derivatives are important intermediates in synthesis of heterocyclic compounds in dyes and pharmaceutical products (Olah et al, 1980).…”

Ikaros expression as a marker for lymphoid progenitors during zebrafish development

“…2‐Substituted free (NH)‐imidazoles include substances that have been identified as potent, partial agonists of the α 1A adrenergic receptor,122 agonists of serotonin receptors,123 antimicrobials,124 selective glycogen synthase kinase 3 inhibitors,125 and selective γ‐aminobutyric acid A receptor ligands 126. Moreover, 2‐(3‐methylpyridyn‐2‐yl)imidazole has found application as a ligand in Pd‐catalyzed reactions 127…”

Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT1A Receptors

“…These findings prompted us to extend the Csp 3 -4 replacement of hydrogen by fluorine to other ligands of this family. 7 The compounds shown in Table 2 could be separated into two groups: (1) derivatives bearing an aliphatic amino substituent in the 6-position of the pyridine ring and (2) those having a five-membered heteroaromatic ring in this position. Within the first group (23-25, 28b Although the influence of the C-4 fluorine on the oral performance of the compounds shared the positive trend seen in the first group, there were marked differences among members of this group in terms of their in vitro potency (pEC 50 ).…”

“…7 The synthesis of the novel 5-methyl-6-substituted-2-pyridinecarboxaldehydes was carried out as depicted in Scheme 7. The ester 16, obtained by the method of Hoornaert, 15 was reduced to the alcohol 17.…”