Aminoalkylpyridines (AAPs), Triazoline Metabolite Analogues, As Anticonvulsants Highly Effective in the Mes Test

Abstract

Elucidation of the metabolism and pharmacology of 1,2,3-triazolines (TRs) led to the identification of the triazoline pharmacophore and the evolution of the aminoalkylpyridines (AAPs). The AAPs have no activity in the scMet test but are highly effective in the MES seizure test by the oral route. The AAPs bind to the sigma(1) receptor with low affinity, but high selectivity. They impair Glu release to the same extent as the triazolines and afforded a high degree of protection in the kindled rat. They show no affinity for the NMDA/PCP receptor sites; thus the toxic side effects of NMDA antagonists are absent in the sigma selective AAPs. Variations of the heterocyclic unit, the alkyl chain and the amino group in the AAP leads, indicated that the 4-pyridyl substituent along with a methyl (alkyl) group, and a 4-C1, 3-C1 or 3,4-C1(2) substitution on the N-phenyl group, afforded the most active compounds. Amino group modification by acylation did not improve activity. The hydrazone compounds were the most active. Although the AAPs are very effective in the MES and the kindling models of epilepsy, they showed only low to moderate activity in protecting neuronal cells in stroke-induced cerebral ischemia. In the case of the TR compounds, even the least effective TR afforded 47% protection from neuronal injury. It is not known at this point, whether activity in both the MES and scMet tests, which would imply a role for both Glu and GABA, is a prerequisite for antiischemic activity.

Metal-free Three-Component Synthesis of 1,2,3-Triazoline-4-sulfonamides

“…1,2,3-Triazolines and their oxidized 1,2,3-triazole congeners are indisputably important cores for drug design. Whereas 1,2,3-triazolines were investigated as anticonvulsant, anti-ischemic (exemplified by compound 1 or ADD17014), and antiprotozoal (compound 2 ) agents, 1,2,3-triazoles appear to be comparably (if not more) universal scaffolds because they have delivered such valuable bioactive compounds as non-nucleoside reverse transcriptase inhibitor tert -butyldimethylsilylspiroaminooxathioledioxide (TSAO, compound 3 ), antimicrobial and anticancer carboxyamidotriazole (CAI, compound 4 ), and a potent human dUTPase inhibitor 5 for the tumor-selective enhancement of 5-fluorouracil-mediated antiproliferative action (Figure ). Considering the apparently privileged character of these cores, the development of synthetic routes to 1,2,3-triazol­(in)­es with unusual, let alone unexplored, substitution patterns , is clearly worth undertaking because it increases the chances of discovering first-in-class bioactive compounds as leads for drug discovery and ensures that intellectual property rights for such chemotypes can be claimed …”

Amino Acyl Conjugates of Nitrogen Heterocycles as Potential Pharmacophores

“…R-Amino acids and their derivatives are central to the chemistry and biology of peptides and proteins as well as versatile synthetic building blocks for pharmaceutical applications, precursors for the generation of molecular diversity, important templates in asymmetric catalysis, and common subunits in many bioactive compounds and natural products. 1 Pyridine and quinoline scaffolds possess important pharmacological activities including anti-inflammatory, 2,3 anticonvulsant, 4,5 antibacterial, 6,7 antihistaminic, 8 and anticancer. 9 Pyridines substituted by R-aminoacyl groups include useful drugs for osteoporosis and other metabolic bone diseases, 10,11 potent inhibitors of nitric oxide synthase (NOS) isozymes, 12 effective biochemical markers of bone resorption, 13 efficient organogelators, 14 and bacterial growth inhibitors.…”

“…Pyridine and quinoline scaffolds possess important pharmacological activities including anti-inflammatory, , anticonvulsant, , antibacterial, , antihistaminic, and anticancer . Pyridines substituted by α-aminoacyl groups include useful drugs for osteoporosis and other metabolic bone diseases, , potent inhibitors of nitric oxide synthase (NOS) isozymes, effective biochemical markers of bone resorption, efficient organogelators, and bacterial growth inhibitors …”