title: Synthesis, structural activity-relationships, and biological evaluation of novel amide-based allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
abstract: The synthesis and structure-activity relationship analysis of a novel class of amide-based biaryl NR2B-selective NMDA receptor antagonists are presented. Some of the studied compounds are potent, selective, non-competitive, and voltage-independent antagonists of NR2B-containing NMDA receptors. Like the founding member of this class of antagonists (ifenprodil), several interesting compounds of the series bind to the amino terminal domain of the NR2B subunit to inhibit function. Analogue potency is modulated by linker length, flexibility, and hydrogen bonding opportunities. However, unlike previously described classes of NR2B-selective NMDA antagonists that exhibit off-target activity at a variety of monoamine receptors, the compounds described herein show much diminished effects against the hERG channel and alpha(1)-adrenergic receptors. Selections of the compounds discussed have acceptable half-lives in vivo and are predicted to permeate the blood-brain barrier. These data together suggest that masking charged atoms on the linker region of NR2B-selective antagonists can decrease undesirable side effects while still maintaining on-target potency.
authors: Department of Chemistry, Emory University, Atlanta, GA, USA.
authors: Cara A
authors: CA
authors: Mosley
authors: Scott J
authors: SJ
authors: Myers
authors: Ernest E
authors: EE
authors: Murray
authors: Rose
authors: R
authors: Santangelo
authors: Yesim A
authors: YA
authors: Tahirovic
authors: Natalie
authors: N
authors: Kurtkaya
authors: Praseeda
authors: P
authors: Mullasseril
authors: Hongjie
authors: H
authors: Yuan
authors: Polina
authors: P
authors: Lyuboslavsky
authors: Phuong
authors: P
authors: Le
authors: Lawrence J
authors: LJ
authors: Wilson
authors: Manuel
authors: M
authors: Yepes
authors: Ray
authors: R
authors: Dingledine
authors: Stephen F
authors: SF
authors: Traynelis
authors: Dennis C
authors: DC
authors: Liotta
mesh_terms: D000495:Allosteric Site; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004285:Dogs; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D000577:Amides; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate