IN-VITRO AND IN-VIVO PREDICTORS OF THE ANTIEMETIC ACTIVITY OF TACHYKININ NK1 RECEPTOR ANTAGONISTS

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro(9),Me-Leu(8)]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced b y cisplatin in ferrets. (+/-)-GR203040 ((2S,3S and razol-1-yl-benzyl-( 2-phenyl-piperidin-3-yl)amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxyben zylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 phenyl- 4-(5-(3-oxo-12,4-triazolo)methylmorpholine) potently inhibited GR73632 -induced foot tapping (ID50 < 0.85 mg/kg), and acute retching induced by cisplatin (ID50 less than or equal to 0.18 mg/kg). RPR100893 thoxyp henyl)-2-[(S)-2-(2-methoxyphenyl)proprionyl] perhydroisoindol-4-ol) wa s not a potent antaonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50 > 10 mg /kg). High doses (3-10 mg/kg) of CGP49823 benzoyl)-N-[(4 -quinolinyl)methyl]-4-piperineamine) dihydrochloride), FK888 (N-2-[(4R )-4-hydroxy- thyl-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY 303870 -(piperidinyl)piperidin-1-yl)acetyl)amino]propane) were require d to inhibit foot tapping; these agents were not anti-emetic in this d ose range. SR140333 ((S)-1-{2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyph enylacetyl)piperidin-3-yl] ethyl}-4-phenyl-1 azaniabicyclo[2.2.2]octan e; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities fo r the human and ferret tachykinin NK1 receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-emetic activity in ferr ets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.