Novel 3‐Carboxy‐ and 3‐Phosphonopyrazoline Amino Acids as Potent and Selective NMDA Receptor Antagonists: Design, Synthesis, and Pharmacological Characterization

Conti, Paola; Pinto, Andrea; Tamborini, Lucia; Madsen, Ulf; Nielsen, Birgitte; Bräuner‐Osborne, Hans; Hansen, Kasper B.; Landucci, Elisa; Pellegrini‐Giampietro, Domenico E.; Sarro, Giovambattista De; Paola, Eugenio Donato Di; Micheli, Carlo De

doi:10.1002/cmdc.201000184

Cited by 22 publications

(17 citation statements)

References 31 publications

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“…In this study, we explore the structural and pharmacological properties of a series of ligands based on (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) (22). Competitive NMDA receptor antagonists in this series have been evaluated as potential neuroprotective and radioligand imaging agents (22,23).…”

Section: Significancementioning

confidence: 99%

“…Competitive NMDA receptor antagonists in this series have been evaluated as potential neuroprotective and radioligand imaging agents (22,23). Furthermore, preliminary functional results suggested that addition of halogen substituents to one of these ligands, FRA-19 {(S)-5-[(R)-2-amino-2-carboxyethyl]-1-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid}, resulted in modest preference for GluN1/2A over GluN1/2B receptors, as seen for compounds ST1 {(S)-5-[(R)-2-amino-2-carboxyethyl]-1-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid} and ST6 {(S)-5-[(R)-2-amino-2-carboxyethyl)-1-(4-bromophenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid} (23).…”

Section: Significancementioning

confidence: 99%

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Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Lind

Mou

Tamborini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.

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Section: Significancementioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Lind

Mou

Tamborini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In this study, we examined the neuroprotective effects of Bv8 in murine cortical cell cultures and in organotypic hippocampal slices exposed to OGD, two in vitro models of cerebral ischemia routinely in use in our laboratory that allow chronic treatment with drugs in a relatively isolated environment that closely reproduces what occurs in vivo (Conti et al, 2010;Gerace et al, 2012a). We also examined the role of prokineticins in the induction of OGD tolerance and the expression of prokineticins and prokineticin receptors following NMDA preconditioning in organotypic hippocampal slices.…”

Section: Introductionmentioning

confidence: 99%

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

Landucci

Lattanzi²,

Gerace

et al. 2016

Neuropharmacology

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“…Furthermore, preliminary evaluation of GluN2 subunit selectivity suggested that the racemic mixture (±)-3 displayed a preference for inhibition of NMDA receptors containing GluN2A or GluN2B subunits compared to receptors with GluN2C or GluN2D subunits. 10 …”

Section: Introductionmentioning

confidence: 99%

Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

et al. 2016

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Abnormal activity of various N-methyl-d-aspartate receptor (NMDAR) subtypes has been implicated in a wide variety of neurological disorders such as Alzheimer's disease, schizophrenia, and epilepsy. Imaging agents for PET and SPECT that target NMDARs in a subtype-selective fashion may enable better characterization of those disorders and enhance drug development. On the basis of a pyrazoline derivative that demonstrated neuroprotective effects in vivo, we synthesized a series of para-substituted analogues and measured their affinities to various NMDAR subtypes. Compounds 4a–c and 4e showed greater, nanomolar affinity for the GluN1/2A subtype versus GluN1/2B. Dicarbomethoxy (pro-drug) analogues of [124/125I]4d and [11C] 4e (i.e., [124/125I]11d and [11C]11e) were generated and tested for NMDAR binding specificity in ex vivo autoradiography and brain biodistribution studies. Although NMDAR-specific binding could be demonstrated for [125I]11d and [11C]11e through autoradiography and biodistribution studies, imaging of neither [124I]11d nor [11C]11e could demonstrate brain penetration sufficient for detection by PET.

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Novel 3‐Carboxy‐ and 3‐Phosphonopyrazoline Amino Acids as Potent and Selective NMDA Receptor Antagonists: Design, Synthesis, and Pharmacological Characterization

Cited by 22 publications

References 31 publications

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

Development of Radiolabeled Ligands Targeting the Glutamate Binding Site of the N-Methyl-d-aspartate Receptor as Potential Imaging Agents for Brain

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