Insights into Structure-Activity Relationships and CNS Therapeutic Applications of NR2B Selective Antagonists

C.      Beinat; S.      Banister; I.      Moussa; A.      J. Reynolds; C.      S.P. McErlean; M.      Kassiou

doi:10.2174/092986710793348572

Abstract

Excessive stimulation of NMDA receptors is involved in various CNS pathologies such as Parkinsons disease, acute and chronic pain and cerebral ischaemia. The use of NMDA antagonists as therapeutic agents has been restricted as a result of unwanted side effects including hallucinations and loss of co-ordination. NR2B subtype selective antagonists have previously shown a therapeutic effect without causing the side effects of broad spectrum NMDA antagonists. Considerable research has since been devoted to the development of orally bioavailable, selective NR2B antagonists and their applications in various neurological diseases. The improved therapeutic index of these compounds is expected to be the result of the subtype selectivity and cellular location of the NR2B receptors within the CNS. This review describes recent advances in the development of NR2B antagonists as well as their therapeutic applications.

Keywords: NR2B, Antagonist, NMDA receptors, Neurological disease, CNS, Structure-activity relationships, NR2B Selective Antagonists, metabotropic glutamate, dysphoria, extrasynaptically, extrasynaptic NR2B, pharmacokinetics, ifenprodil pharmacophore, 3,4-difluoro-substitution, Various Cinnamidines, phenylpropyl subunit, naphthamidine, cinnamidine-based NR2B, Pharmacokinetic Data, 4-trifluoromethoxy, hyperalgesia, autoradiography, cinnamidines, trifluoromethoxyphenyl, aforementioned, SAfiRs, pharmacokinetic, repolarization, rigidification, piperidines, NMDA antagonists, antinociceptive, Kynurenic Acid Amides, 7-hydroxy analogue, discriminate, thiadiazolyl, Aminoheterocycle Derivatives, carageenan-induced, anti-nociceptive effects, allodynia, cyclohexane, Heterocycles, Cyclohexanol Phenols, cyclohexane derivatives, mousepartial-sciatic-nerve-ligation, 4-dihydroquinolinon, lipophilic, Aniline, Enantiomeric Propanolamines, Tahirovic, enantiomeric propranolamines, 4-methylsulfonamide, isobutyl, enantioselectivity, hydroxyl group, Propanolamines, discrimination, homopiperidine, Heterocyclic, thiosemicarbazide, Ethylenediamine, Affinities, noradrenalin, excitotoxicity, NEUROLOGICAL, L-DOPA therapy, anti-Parkinsonian effects, sensorimotor, Immunocytochemical, Ifenprodil, neuroprotective effects, Huntington's Disease, neurodegeneration, Alzheimer's Disease, glutamate, psychomimetic, epileptiform, intraperitoneal, paroxysmal disorder, polycyclic units, in vivo evaluation