Solid-supported synthesis and 5-HT7/5-HT1A receptor affinity of arylpiperazinylbutyl derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one

Chemical Biology & Drug Design, 2015, Volume: 86, Issue: 4, Pages: 697-703,  DOI: 10.1111/cbdd.12539

K. Grychowska, N. Masurier, P. Verdie, G. Satala, A. J. Bojarski, J. Martinez,  M. Pawlowski, G. Subra, P. Zajdel

Abstract

A series of arylpiperazinylbutyl derivs. I [R¹ = H, 2-OMe, 2-SMe, 2-F, 4-Cl, 2,3-diCl; R² = Ph, 2-ClC₆H₄, cyclohexyl] of 4,5-dihydro-1,2,4-triazine-6(1H)-ones was designed and synthesized according to the new solid-supported methodol.  In this approach, triazinone scaffold was constructed from the fmoc-protected glycine.  The library representatives showed different levels of affinity for 5-HT₇ and 5-HT_1A receptors, among which compds. I [R¹ = 2-SMe, 2-F; R² = Ph and R¹ = 2-OMe, 2-SMe, 2,3-diCl; R² = cyclohexyl] were classified as dual 5-HT₇/5-HT_1A receptors ligands.  The structure-affinity relationship anal. revealed that receptor affinity and selectivity of the tested compds. depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of phenylpiperazine moiety.