Enantiomeric Propanolamines as selectiveN-Methyl-d-aspartate 2B Receptor Antagonists

Abstract

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.

Mapping the Binding of GluN2B-SelectiveN-Methyl-d-aspartate Receptor Negative Allosteric Modulators

“…1B) are critical to activity Menniti, 1999, Tahirovic et al, 2008). Molecules lacking this ring are inactive (e.g., compound 6 in Chenard et al, 1991), and substitutions on this ring, such as dichloro in the case of propanolamines, strongly control potency (Tahirovic et al, 2008). The binding interface representing the hydrophobic A ring consists of residues from the R1 domains of both the GluN1 (Ala75, Tyr109, and Thr110) and GluN2B subunits (Pro78, Ile82, Ile111, and Phe114; Figs.…”

“…C, summary of the sequence similarity between the different GluN2 subunits. pounds docked, several series have demonstrated strongly enhanced potency with dichlorosubstituted A rings (Tahirovic et al, 2008;Mosley et al, 2010). For example, a 3,4-dichloro substitution of the benzene A ring increased the activity within two series of compounds by more than 100-fold (Tahirovic et al, 2008;Mosely et al, 2009).…”

“…Ifenprodil hemitartrate (erythro enantiomers; Tocris, Ellisville, MO or Ascent Scientific, Princeton NJ), ␣-(4-hydroxyphenyl)-␤-methyl-4-(phenylmethyl)-1-piperidine propanol (Ro-25-6981; Ascent Scientific), eliprodil (Tocris), and traxoprodil (CP101,606; Axon MedChem, Groningen, Netherlands) were made as 20 to 100 mM stocks in dimethyl sulfoxide and diluted to the desired concentration; final dimethyl sulfoxide content was never greater than 0.1% for all solutions. Compound 29 was synthesized as described in Tahirovic et al (2008). Compounds 15, 49, and 68 were synthesized as described by Mosley et al (2009).…”

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…Similar to Zn 2ϩ binding to the ATD of GluN2A (see section VI.E), ifenprodil increases the potency of proton inhibition of NMDA receptors Mott et al, 1998). Rich pharmacology exists for this site, with nearly a dozen structural classes described, including oxamides (Barta-Szalai et al, 2004), 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines (Bü ttelmann et al, 2003), benzamidines (Claiborne et al, 2003), 5-substituted benzimidazoles (McCauley et al, 2004), indole-2-carboxamides (Borza et al, 2006(Borza et al, , 2007, benzyl cinnamamidines (Tamiz et al, 1999;Curtis et al, 2003), and other biaryl analogs (Tamiz et al, 1998;Wright et al, 2000;Tahirovic et al, 2008;Mosley et al, 2009). …”

“…However, development of GluN2B-selective antagonists has been hindered by their activity at ␣1-adrenergic receptors, serotonin receptors, calcium channels, and hERG potassium channels . The problem of target selectivity has been partially overcome by potent ifenprodil analogs such as Ro 25-6981 and CP-101,606 (Fischer et al, 1997; Taniguchi et al, 1997; Tahirovic et al, 2008). Off-target activity at hERG channels by GluN2B antagonists is decreased by eliminating basic nitrogen atoms; increasing the number of oxygen atoms within the linker of GluN2B antagonists also decreases affinity for hERG channels and ␣1-adrenergic receptors (Kawai et al, 2007;Mosley et al, 2009).…”