PT  - JOURNAL ARTICLE
AU  - Ruth A. Duffy
AU  - Geoffrey B. Varty
AU  - Cynthia A. Morgan
AU  - Jean E. Lachowicz
TI  - Correlation of Neurokinin (NK) 1 Receptor Occupancy in Gerbil Striatum with Behavioral Effects of NK1 Antagonists
AID  - 10.1124/jpet.301.2.536
DP  - 2002 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 536--542
VI  - 301
IP  - 2
4099  - http://jpet.aspetjournals.org/content/301/2/536.short
4100  - http://jpet.aspetjournals.org/content/301/2/536.full
SO  - J Pharmacol Exp Ther2002 May 01; 301
AB  - 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 [H2N-(CH2)4-CO-Phe-Pro-NMe-Leu-Met-NH2] 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 IC50 values for inhibition of ex vivo125I-substance P binding by NK1 antagonists were compared with the corresponding EC50 values for inhibition of GFT, a significant positive correlation was observed (r2 = 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 IC50 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. The American Society for Pharmacology and Experimental Therapeutics