Document Detail

Correlation of neurokinin (NK) 1 receptor occupancy in gerbil striatum with behavioral effects of NK1 antagonists.
MedLine Citation:
PMID:  11961054     Owner:  NLM     Status:  MEDLINE    
Interest in central neurokinin (NK) 1 receptors has increased based on reports of the therapeutic potential for NK1 antagonists in anxiety and depression. In these studies, an ex vivo binding procedure was used to correlate NK1 receptor occupancy in striatum by NK1 antagonists with their potency to inhibit NK1 agonist-induced foot tapping in gerbils (GFT). The following compounds were administered orally: CP-99,994 [(+)-cis-n-[(2-methoxyphenyl)methyl]-2-phenyl-3-piperidinamine), L-742,694 [5-[[2(S)-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-3(S)-phenyl-4-morpholinyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one]), MK-869 [5-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one], CP-122,721 [cis-n-[[2-methoxy-5-(trifluoromethoxy)phenyl]methyl]-2-phenyl-3-piperidinamine], L-760,735-F [4-[[2(R)-[1(R)-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)-4-morpholinyl]methyl]-N,N-dimethyl-1H-1,2,3-triazole-5- methanamine], GR205171 [N-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]phenyl]methy]-2(S)-phenyl-3(S)-piperidinamine], L-733,060 [(2S,3S)3-([3,5-bis(trifluoro methyl)phenyl]methoxy)-2-phenylpiperidine], and L-733,061 [(2R,3R)-3-([3,5-bis(trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine]. Two hours later, gerbils received the NK1 agonist GR73632 [H(2)N-(CH(2))(4)-CO-Phe-Pro-NMe-Leu-Met-NH(2)] i.c.v. and foot tapping was measured for 5 min. The same procedure was used for ex vivo binding studies except that saline, rather than agonist, was administered i.c.v. before dissection of the striatum. The tissue homogenate was then used in an equilibrium radioligand binding assay. When IC(50) values for inhibition of ex vivo (125)I-substance P binding by NK1 antagonists were compared with the corresponding EC(50) values for inhibition of GFT, a significant positive correlation was observed (r(2) = 0.97, p < 0.001). This result indicates that increased NK1 receptor occupancy in striatum by NK1 antagonists parallels the inhibition of agonist-mediated GFT. For all compounds, the dose that produced the maximum inhibition of GFT resulted in less than 100% ex vivo receptor occupancy in striatum. When gerbils did not receive the i.c.v. saline injection before ex vivo binding, thereby leaving the blood-brain barrier (BBB) intact, the IC(50) values for antagonists were unchanged, suggesting that potential damage to the BBB caused by the i.c.v. injection did not affect determinations of antagonist potency in the GFT model.
Ruth A Duffy; Geoffrey B Varty; Cynthia A Morgan; Jean E Lachowicz
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  301     ISSN:  0022-3565     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2002 May 
Date Detail:
Created Date:  2002-04-18     Completed Date:  2002-05-13     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  536-42     Citation Subset:  IM    
Central Nervous System/Cardiovascular Pharmacology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
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MeSH Terms
Anti-Anxiety Agents / pharmacology*
Behavior, Animal / drug effects*
Corpus Striatum / drug effects*,  metabolism
Morpholines / pharmacology
Piperidines / pharmacology
Receptors, Neurokinin-1 / antagonists & inhibitors,  metabolism*
Statistics as Topic
Reg. No./Substance:
0/Anti-Anxiety Agents; 0/L 742694; 0/L 760735; 0/Morpholines; 0/Piperidines; 0/Receptors, Neurokinin-1; 148700-85-0/3-((3,5-bis(trifluoromethyl)phenyl)methyloxy)-2-phenylpiperidine; 1NF15YR6UY/aprepitant

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