SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin 1 receptor: II. Neurochemical and behavioral characterization.
SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a new nonpeptide tachykinin neurokinin 1 (NK1) receptor antagonist, was evaluated against the neurochemical, electrophysiological, and behavioral effects provoked by direct activation of brain tachykinin NK1 receptors or by stress in guinea pigs. SSR240600 (0.1-10 mg/kg i.p. or p.o.) antagonized the excitatory effect of i.c.v. infusion of [Sar(9),Met(O2)(11)]substance P (SP) on the release of acetylcholine in the striatum of anesthetized and awake guinea pigs. This antagonistic action was still observed after repeated administration of SSR240600 (5 days, 10 mg/kg p.o., once a day). SSR240600 (10 mg/kg i.p.) inhibited the phosphorylation of the cAMP response element-binding protein in various brain regions induced by i.c.v. administration of [Sar9,Met(O2)(11)]SP. In slice preparations, neuronal firing of the locus coeruleus (LC) neurons elicited by the application of [Sar9,Met(O2)(11)]SP was suppressed by SSR240600 at 100 nM. Norepinephrine release in the prefrontal cortex, elicited either by an intra-LC application of [Sar9,Met(O2)(11)]SP or by an i.c.v administration of corticotropin-releasing factor, was reduced by SSR240600 (0.3-1 mg/kg and 1-10 mg/kg i.p., respectively). SSR240600 (1-10 mg/kg i.p.) inhibited vocalizations induced in adult guinea pigs by an i.c.v. administration of the NK1 receptor agonist, GR73632 [D-Ala-[L-Pro9,Me-Leu8]substance P(7-11)]. Furthermore, SSR240600 (1-10 mg/kg i.p.) inhibited distress vocalizations produced in guinea pig pups by maternal separation. SSR240600 also reduced maternal separation-induced increase in the number of neurons displaying NK1 receptor internalization in the amygdala. Finally, SSR240600 counteracted the increase in body temperature induced by isolation stress. In conclusion, SSR240600 is able to antagonize various NK1 receptor-mediated as well as stress-mediated effects in the guinea pig.
Steinberg
Régis
R
C.N.S. Research Department, Sanofi-Synthélabo Recherche, Montpellier, France. regis.steinberg@sanofi-synthelabo.com
Alonso
Richard
R
Rouquier
Liliane
L
Desvignes
Christophe
C
Michaud
Jean-Claude
JC
Cudennec
Annie
A
Jung
Mireille
M
Simiand
Jacques
J
Griebel
Guy
G
Emonds-Alt
Xavier
X
Le Fur
Gérard
G
Soubrié
Philippe
P
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009025:Morpholines / Q000737:chemistry / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000819:agonists / Q000378:metabolism*; D014828:Vocalization, Animal / Q000187:drug effects* / Q000502:physiology
C469681:2-(1-(2-(4-(2-(3,5-bis(trifluoromethyl)phenyl)acetyl)-2-(3,4-dichlorophenyl)-2-morpholinyl)ethyl)-4-piperidinyl)-2-methylpropanamide; D017362:Cyclic AMP Response Element-Binding Protein; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D000109:Acetylcholine; D009638:Norepinephrine