Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists

We attempted to establish and validate an in vivo pharmacodynamic (pd) rabbit model to screen tachykinin nk2 receptor (nk2-r) antagonists using pharmacological and pharmacokinetic (pk)/pd analyses. under urethane anesthesia,changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective nk2-r agonist,βala8-neurokinin a(4-10) (βa-nka),was monitored as a pd marker. the analgesic effects of nk2-r antagonists were evaluated by monitoring visceromotor response (vmr) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. intravenous administration of βa-nka induced transient colonic contractions dose-dependently,which were inhibited by the selective nk 2-r antagonists in dose- and/or plasma concentration-dependent manners. the correlation between pd inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r2 = 0.61). furthermore,the minimum effective doses on the vmr and id50 values calculated in the pd model were highly correlated (r 2 = 0.74). in conclusion,we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for nk 2-r antagonists. in a drug discovery process,this pd model could enhance the therapeutic candidate selection for irritable bowel syndrome,pharmacologically connecting in vitro affinity for nk2-r with in vivo therapeutic efficacy. © the japanese pharmacological society.