THE POTENCY OF THE NOVEL TACHYKININ RECEPTOR ANTAGONIST CGP49823 AT RAT AND GERBIL MOTONEURONS IN-VITRO

The novel tachykinin receptor antagonist CGP44823 ylbenzoyl)-4-(quinol in-4-ylmethylamino)piperidine) has been compared with three other sele ctive non-peptide tachykinin NK1 receptor antagonists. The drugs were tested as antagonists of the depolarization of spinal motoneurones ind uced by bath application of the selective tachykinin NK1 receptor agon ist septide-(6-11)(300 nM) for 120 s at 15 min intervals. The antagoni sts were bath applied and the depolarizations were recorded from lumba r ventral roots of 7 to 12 day old rat and gerbil hemisected spinal co rds in vitro. The gerbil preparation is considered to model the human species variant of the tachykinin NK1 receptor. With the exception of SR140333 (3,4-dichlorophenyl)-1-[[3-(1-methylethoxy)phenyl] acetyl]-3- piperidinyl)]-4-phenyl-1-azoniabicyclo [2.2.2]octanechloride), the ant agonists were approximately thirty-fold more potent on gerbil preparat ions. The respective mean IC50 values from gerbil preparations produce d by CP96345 ((2S-cis)-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl] -1-azabicyclo[2.2.2]octan-3-amine), CGP49823, SR140333 and CP99994 2-m ethoxyphenyl)methyl]-2-phenyl-3-piperidinamine) were, in mu M +/- S.E. (n) 0.10 +/- 0.02 (6), 0.22 +/- 0.03 (6), 0.30 +/- 0.10 (5) and 0.38 +/- 0.02 (5) and the corresponding values from the rat preparations we re 3.7 +/- 0.4 (5), 7.8 +/- 1.3 (5), 1.06 +/- 0.16 (6) and 10.5 +/- 2. 2 (7). Dominance of tachykinin NK1 receptor activity in the measured r esponses was confirmed by low potency of the tachykinin NK2-selective antagonist SR48968 ((S)-N-methyl-N[4-(4-acetylamino-3-phenyl piperidin o)-2-(3,4-dichlorophenyl)butyl] benzamide) which yielded an IC50 value of 12.0 +/- 2.8 (5) on gerbil preparations and produced less than 50% depression of septide-induced depolarization of rat motoneurones at t he highest concentration (100 mu M) tested. (C) 1998 Elsevier Science B.V.