Enantiomeric Propanolamines as selective N-Methyl-d-aspartate 2B Receptor Antagonists

• Published in: Journal of medicinal chemistry Vol. 51; no. 18; pp. 5506 - 5521
• Main Authors: Tahirovic, Yesim A, Geballe, Matthew, Gruszecka-Kowalik, Ewa, Myers, Scott J, Lyuboslavsky, Polina, Le, Phuong, French, Adam, Irier, Hasan, Choi, Woo-baeg, Easterling, Keith, Yuan, Hongjie, Wilson, Lawrence J, Kotloski, Robert, McNamara, James O, Dingledine, Raymond, Liotta, Dennis C, Traynelis, Stephen F, Snyder, James P
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.09.2008; Amer Chemical Soc
• Subjects: Animals; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Biological and medical sciences; Blood-Brain Barrier; Brain - metabolism; Chemistry, Medicinal; Excitatory Amino Acid Antagonists - blood; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacokinetics; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Motor Activity - drug effects; Neuropharmacology; Neuroprotective agent; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Propanolamines - blood; Propanolamines - chemistry; Propanolamines - pharmacokinetics; Propanolamines - pharmacology; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Xenopus; NMDA RECEPTOR; NR2B SUBUNIT; CHEMOSELECTIVE HYDROGENATION; GLUTAMATE; FOCAL CEREBRAL-ISCHEMIA; ZINC INHIBITION; CELL-CULTURE; RAT-BRAIN; BINDING; MOLECULAR-FORCE FIELD; Intraperitoneal administration; Rat; Anticonvulsant; Glutamate receptor; Selectivity; Modeling; Hydroxyether; Structure activity relation; Chlorine Organic compounds; Enantiomer; Molecular model; Antagonist; Aminoalcohol; Sulfonamide; Rodentia; Benzene derivatives; Neuroprotective agent; In vitro; In vivo; Locomotion; Vertebrata; Mammalia; Mouse; Animal; Affinity; NMDA receptor; Electrostatic model
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8002153

Enantiomeric propanolamines have been identified as a new class of NR2B-selective NMDA receptor antagonists. The most effective agents are biaryl structures, synthesized in six steps with overall yields ranging from 11−64%. The compounds are potent and selective inhibitors of NR2B-containing recombinant NMDA receptors with IC50 values between 30−100 nM. Potency is strongly controlled by substitution on both rings and the centrally located amine nitrogen. SAR analysis suggests that well-balanced polarity and chain-length factors provide the greatest inhibitory potency. Structural comparisons based on 3D shape analysis and electrostatic complementarity support this conclusion. The antagonists are neuroprotective in both in vitro and in vivo models of ischemic cell death. In addition, some compounds exhibit anticonvulsant properties. Unlike earlier generation NMDA receptor antagonists and some NR2B-selective antagonists, the present series of propanolamines does not cause increased locomotion in rodents. Thus, the NR2B-selective antagonists exhibit a range of therapeutically interesting properties.