title: Subtype-selective N-methyl-D-aspartate receptor antagonists: synthesis and biological evaluation of 1-(heteroarylalkynyl)-4-benzylpiperidines.
abstract: 4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]phenol (9) are potent NR1A/2B receptor antagonists (IC(50) values 0.17 and 0.10 microM, respectively). Administered intraperitoneally, they both potentiated the activity of L-DOPA in the unilaterally 6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson's disease. However, compound 9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones gave equipotent or more potent analogues. The preference for a para arrangement between the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the piperidine had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demonstrated slightly improved selectivity for NR1A/2B receptors versus alpha-1 adrenergic and dopamine D2 receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1, 3-dihydrobenzoimidazol-2-one (46b) was identified as a very potent, selective NR1A/2B receptor antagonist (IC(50) value 0.0053 microM). After oral administration at 10 and 30 mg/kg, 46b potentiated the effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability but lower brain penetration compared to phenol 9.
authors.affiliation: CoCensys, Inc., 213 Technology Drive, Irvine, California 92618, USA. jonathan.wright@pfizer.com
authors.forename: J L
authors.initials: JL
authors.lastname: Wright
authors.forename: T F
authors.initials: TF
authors.lastname: Gregory
authors.forename: S R
authors.initials: SR
authors.lastname: Kesten
authors.forename: P A
authors.initials: PA
authors.lastname: Boxer
authors.forename: K A
authors.initials: KA
authors.lastname: Serpa
authors.forename: L T
authors.initials: LT
authors.lastname: Meltzer
authors.forename: L D
authors.initials: LD
authors.lastname: Wise
authors.forename: S A
authors.initials: SA
authors.lastname: Espitia
authors.forename: C S
authors.initials: CS
authors.lastname: Konkoy
authors.forename: E R
authors.initials: ER
authors.lastname: Whittemore
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C413888:5-(3-(4-benzylpiperidin-1-yl)prop-1-ynyl)-1,3-dihydrobenzimidazol-2-one; D000978:Antiparkinson Agents; D001562:Benzimidazoles; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate