title: Structure function differences in nonpeptide CCR1 antagonists for human and mouse CCR1.
abstract: A useful strategy for identifying ligand binding domains of G protein-coupled receptors has been the exploitation of species differences in antagonist potencies. We have used this approach for the CCR1 chemokine receptor with a novel series of antagonists, the 4-hydroxypiperidines, which were discovered by high throughput screening of human CCR1 and subsequently optimized. The structure-activity relationships for a number of different 4-hydroxypiperidine antagonists for human and mouse CCR1 were examined by receptor binding and functional assays. These compounds exhibit major differences in their rank order of potency for the human and mouse chemokine receptor CCR1. For example, the initial lead template, BX 510, which was a highly potent functional antagonist for human CCR1 (K(i) = 21 nM) was >400-fold less active on mouse CCR1 (K(i) = 9150 nM). However, increasing the length of the linker between the piperidine and dibenzothiepine groups by one methylene group generated a compound, BX 511, which was equipotent for both human and mouse CCR1. These and other analogs of the lead template BX 510, which have major differences in potency for human and mouse CCR1, are described, and a model for their interaction with human CCR1 is presented.
authors.affiliation: Department of Immunology, Berlex Biosciences, 2600 Hilltop Drive, Richmond, CA 94806, USA.
authors.forename: James
authors.initials: J
authors.lastname: Onuffer
authors.forename: Margaret A
authors.initials: MA
authors.lastname: McCarrick
authors.forename: Laura
authors.initials: L
authors.lastname: Dunning
authors.forename: Meina
authors.initials: M
authors.lastname: Liang
authors.forename: Mary
authors.initials: M
authors.lastname: Rosser
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Wei
authors.forename: Howard
authors.initials: H
authors.lastname: Ng
authors.forename: Richard
authors.initials: R
authors.lastname: Horuk
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002417:Cattle; D002460:Cell Line; D003198:Computer Simulation; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: C406591:2,2-diphenyl-(5-(4-chlorophenyl)piperidin-1-yl)valeronitrile; C401389:4-(4-chlorophenyl)-4-hydroxy-alpha,alpha-diphenyl-1-piperidinepentanenitrile; C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D009570:Nitriles; D010879:Piperazines; D010880:Piperidines; D054389:Receptors, CCR1; D019707:Receptors, Chemokine