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 NK(2) receptor (NK(2)-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 NK(2)-R agonist, ßAla(8)-neurokinin A(4-10) (ßA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-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 ßA-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 (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) 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 NK(2)-R with in vivo therapeutic efficacy.

Effects of TAK-480, a novel tachykinin NK(2)-receptor antagonist, on visceral hypersensitivity in rabbits and ricinoleic acid-induced defecation in guinea pigs.

TAK-480, 4-(difluoromethoxy)-N-((1R,2S)-2-(((3aR,4R,9bR)-4-(methoxymethyl)-2, 3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl)carbonyl)cyclohexyl)benzamide, is a novel tachykinin NK(2)-receptor antagonist. In this study, we investigated its antagonistic activity and efficacy in animal models of visceral hypersensitivity and stimulated bowel function which have been implicated to underlie the symptoms in irritable bowel syndrome (IBS). TAK-480 showed potent binding affinity for human NK(2) receptors with a marked species difference and a 10,000-fold selectivity versus NK(1) and NK(3) receptors. TAK-480 dose-dependently antagonized colonic contractions induced by administration of the NK(2) receptor-selective agonist beta-Ala(8)-NKA(4-10) (ßA-NKA) in anesthetized rabbits. In a rabbit model of intracolonic zymosan-induced visceral hypersensitivity, TAK-480 markedly inhibited the visceromotor response to colorectal distension, in contrast to the moderate inhibition by the serotonin 5-HT(3)-receptor antagonist alosetron. In addition, TAK-480 suppressed ricinoleic acid-induced defecation without affecting spontaneous defecation in guinea pigs, whereas alosetron suppressed both. Furthermore, TAK-480 inhibited smooth muscle contractions produced by natural tachykinins (substance P, neurokinin A, and neurokinin B) as well as ßA-NKA in an isolated human colon. In conclusion, the novel NK(2)-receptor antagonist TAK-480 improved visceral hypersensitivity and accelerated defecation without causing constipation in experimental animals. Furthermore, the potent functional blockade of NK(2) receptors in human colon might suggest the potential effectiveness of TAK-480 in IBS patients.

Theoretical and experimental study on the in-plane S(N)2-type substitution reaction of haloalkenes with inversion of configuration at the sp(2) carbon.

[reaction: see text] The intramolecular in-plane S(N)2 type reaction of haloalkene E-8a was predicted to be a facile process for the first time by DFT calculations (B3LYP/6-31+G(d),SCRF(dipole, solvent = DMF)) (DeltaG = 14.4 kcal/mol). The prediction was confirmed experimentally. When E-8a was treated with NaH in DMF, benzofuran was obtained in 95% yield. On the other hand, Z-8a was recovered quantitatively even after heating at 110 degrees C.