title: Comparison of the functional blockade of rat substance P (NK1) receptors by GR205171, RP67580, SR140333 and NKP-608.
abstract: Extensive screening of compound libraries was undertaken to identify compounds with high affinity for the rat NK(1) receptor based on inhibition of [(125)I]-substance P binding. RP67580, SR140333, NKP-608 and GR205171 were selected as compounds of interest, with cloned rat NK(1) receptor binding K(i) values of 0.15-1.9 nM. Despite their high binding affinity, NKP-608 and GR205171 exhibited only a moderate functional antagonism of substance P-induced inositol-1-phosphate accumulation and acidification rate at 1 microM using cloned or native rat NK(1) receptors in vitro. The ability of the compounds to penetrate the CNS was determined by inhibition of NK(1) agonist-induced behaviours in gerbils and rats. GR205171 and NKP-608 potently inhibited GR73632-induced foot drumming in gerbils (ID(50) 0.04 and 0.2 mg/kg i.v., respectively). In contrast, RP67580 and SR140333 were poorly brain penetrant in gerbils (no inhibition at 10 mg/kg i.v.) and were not examined further in vivo. In rats, only high doses of GR205171 (10 or 30 mg/kg s.c.) inhibited NK(1) agonist-induced sniffing and hypertension, whilst NKP-608 (1 or 10 mg/kg i.p.) was without effect. GR205171 (3-30 mg/kg s.c.) caused only partial inhibition of separation-induced vocalisations in rat pups, a response that is known to be NK(1) receptor mediated in other species. These observations demonstrate the shortcomings of currently available NK(1) receptor antagonists for rat psychopharmacology assays.
authors.affiliation: Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. nadia_rupniak@merck.com
authors.forename: Nadia M J
authors.initials: NM
authors.lastname: Rupniak
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: Sara
authors.initials: S
authors.lastname: Shepheard
authors.forename: Graham
authors.initials: G
authors.lastname: Bentley
authors.forename: Angela R
authors.initials: AR
authors.lastname: Williams
authors.forename: Alastair
authors.initials: A
authors.lastname: Hill
authors.forename: Christopher
authors.initials: C
authors.lastname: Swain
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.forename: Ruth
authors.initials: R
authors.lastname: Kilburn
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: Marc M
authors.initials: MM
authors.lastname: Kurtz
authors.forename: Kwei-Lan
authors.initials: KL
authors.lastname: Tsao
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Gould
authors.forename: Gary G
authors.initials: GG
authors.lastname: Chicchi
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D005849:Gerbillinae; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D054833:Isoindoles; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology*; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011804:Quinolines; D011812:Quinuclidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; C414491:quinoline-4-carboxylic acid (1-(3,5-bis-trifluoromethylbenzoyl)-2-(4-chlorobenzyl)piperidin-4-yl)amide; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; C085215:SR 140333; C103207:vofopitant