title: The potency of the novel tachykinin receptor antagonist CGP49823 at rat and gerbil motoneurones in vitro.
abstract: The novel tachykinin receptor antagonist CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-4-(quinolin-4-y lmethylamino)piperidine) has been compared with three other selective non-peptide tachykinin NK1 receptor antagonists. The drugs were tested as antagonists of the depolarization of spinal motoneurones induced by bath application of the selective tachykinin NK1 receptor agonist septide-(6-11) (300 nM) for 120 s at 15 min intervals. The antagonists were bath applied and the depolarizations were recorded from lumbar ventral roots of 7 to 12 day old rat and gerbil hemisected spinal cords in vitro. The gerbil preparation is considered to model the human species variant of the tachykinin NK1 receptor. With the exception of SR140333 ((S)-1-[2-[3-(3,4-dichlorophenyl)-1-[[3-(1-methylethoxy)phenyl]ace tyl]-3-piperidinyl]ethyl]-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride), the antagonists were approximately thirty-fold more potent on gerbil preparations. The respective mean IC50 values from gerbil preparations produced by CP96345 ((2S-cis)-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabicy clo[2.2.2]octan-3-amine), CGP49823, SR140333 and CP99994 ((2S-cis)-N-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine) were, in microM +/- 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 were 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 responses was confirmed by low potency of the tachykinin NK2-selective antagonist SR48968 ((S)-N-methyl-N[4-(4-acetylamino-4-phenyl piperidino)-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 the highest concentration (100 microM) tested.
authors.affiliation: Novartis Pharma Inc., NS Research, Basel, Switzerland. mario_f.pozza@pharma.novartis.com
authors.forename: M F
authors.initials: MF
authors.lastname: Pozza
authors.forename: H R
authors.initials: HR
authors.lastname: Olpe
authors.forename: S
authors.initials: S
authors.lastname: Ofner
authors.forename: C
authors.initials: C
authors.lastname: Schoeffel
authors.forename: R H
authors.initials: RH
authors.lastname: Evans
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D005849:Gerbillinae; D066298:In Vitro Techniques; D009046:Motor Neurons / Q000187:drug effects*; D064729:Neurokinin-1 Receptor Antagonists; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; C110064:CGP 49823; D064729:Neurokinin-1 Receptor Antagonists; D009467:Neuromuscular Depolarizing Agents; D010446:Peptide Fragments; D010880:Piperidines; D011804:Quinolines; D018041:Receptors, Neurokinin-2; D018039:Receptors, Tachykinin; D013373:Substance P; C054725:septide; D011761:Pyrrolidonecarboxylic Acid