HALOGENATED TRIAZINEDIONES BEHAVE AS ANTAGONISTS OF PKR1: IN-VITRO AND IN-VIVO PHARMACOLOGICAL CHARACTERIZATIONAbstract
Different prokineticin receptor antagonists, based on the triazinedione scaffold, were synthesized by a new efficient method. Here we demonstrated that 5-benzyl triazinediones substituted in position para of the benzyl group with halogens provide compounds endowed with interesting selectivity for the Prokineticin receptor 1 (PKR1). BRET technology indicates that such substitution results in increased affinity for the PKR1.The affinity for PKR2, always in mM range, was never significantly affected by the para-halogen-benzyl pharmacophores. The analog bearing a para-bromobenzyl pharmacophore (PC-25) displayed the highest affinity for PKR1 (~18 times higher than the reference PC-1 that bears a para-ethyl benzyl group) and the highest selectivity (~300 times). The other halogen substituted analogs (PC-7, PC-18 and PC-35), showed selectivity for PKR1 more than 100 times higher than for PKR2. Using transgenic mice lacking one of the two PKRs we demonstrated that all these compounds were able to abolish the Bv8-induced hyperalgesia in mice still expressing the PKR1 at doses lower than those necessary to abolish hyperalgesia in mice expressing only the PKR2. The dose ratio reflected the in- vitro evaluated receptor selectivity.
R Lattanzi , C Congiu , V Onnis , A Deplano , S Salvadori , V Marconi , D Maftei , A Francioso , C Ambrosio , I Casella , T Costa , G Caltabiano , M T Matsoukas , G Balboni L Negri
Professor of Pharmacology Dept. of Physiology and Pharmacology, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
07 July, 2014
26 September, 2014
20 October, 2013
01 November, 2014