title: Synthesis and pharmacological evaluation of novel octahydro-1H-pyrido[1,2-a]pyrazine as mu-opioid receptor antagonists.
abstract: To better understand structural requirements for a mu ligand of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class to interact with the mu opioid receptor, we have described in the previous article (Le Bourdonnec, B. et al. J. Med. Chem. 2006, 25, 7278-7289) new, constrained analogues of the N-phenethyl derivative 3. One of the active constrained analogues, compound 4, exhibited subnanomolar mu-opioid receptor affinity (K(i) = 0.62 nM) and potent mu-opioid antagonist activity (IC(50) = 0.54 nM). On the basis of structure 4, a new series of mu-opioid receptor antagonists were designed. In these compounds the octahydroquinolizine template of 4 was replaced by an octahydro-1H-pyrido[1,2-a]pyrazine scaffold. The new derivatives were tested for their binding affinities and in vitro functional activity against the cloned human mu-, delta-, and kappa-opioid receptors. From this study, we identified compound 36, which displays high affinity toward the mu-opioid receptor (K(i) = 0.47 nM), potent mu in vitro antagonist activity (IC(50) = 1.8 nM) and improved binding selectivity profile mu/kappa and mu/delta, when compared to 4.
authors.affiliation: Department of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, Pennsylvania 19341, USA. blebourdonnec@adolor.com
authors.forename: Bertrand
authors.initials: B
authors.lastname: Le Bourdonnec
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Goodman
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Graczyk
authors.forename: Serge
authors.initials: S
authors.lastname: Belanger
authors.forename: Pamela R
authors.initials: PR
authors.lastname: Seida
authors.forename: Robert N
authors.initials: RN
authors.lastname: DeHaven
authors.forename: Roland E
authors.initials: RE
authors.lastname: Dolle
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: C517225:3-(7,8-dimethyl-2-(2-chlorobenzyl)octahydro-1H-pyrido(1,2-a)pyrazin-8-yl)phenol; D008024:Ligands; D011719:Pyrazines; D011725:Pyridines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)