Browsing by Author "Arcoria, Paul J."

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    Conformational Analysis of Fluoro-, Chloro-, and Proteo-Alkene Gly-Pro and Pro-Pro Isosteres to Mimic Collagen
    Arcoria, Paul J.; Ware, Rachel I.; Makwana, Sunny V.; Troya, Diego; Etzkorn, Felicia A. (American Chemical Society, 2021-12-30)
    Collagen is the most abundant human protein, with the canonical sequence (Gly-Pro-Hyp)n in its triple helix region. Cis-trans isomerization of the Xaa-Pro amide has made two of these amide bonds the target of alkene replacement: the Gly-Pro and the Pro-Hyp positions. The conformations of Gly-Pro and Pro-Pro (as a Pro-Hyp model) fluoro-, chloro-, and proteo-alkene mimic models were investigated computationally to determine whether these alkenes can stabilize the polyproline type II (PPII) conformation of collagen. Second-order Møller-Plesset (MP2) calculations with various basis sets were used to perform the conformational analyses and locate stationary points. The calculation results predict that fluoro- and chloro-alkene mimics of Gly-Pro and Pro-Pro can participate in n→π* donation to stabilize PPII conformations, yet they are poor n→π* acceptors, shifting the global minima away from PPII conformations. For the proteo-alkene mimics, the lack of significant n→π* interactions and unstable PPII-like geometries explains their known destabilization of the triple helix in collagen-like peptides.
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    Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N-Methyl-d-aspartate Receptor
    D'Erasmo, Michael P.; Akins, Nicholas S.; Ma, Peipei; Jing, Yao; Swanger, Sharon A.; Sharma, Savita K.; Bartsch, Perry W.; Menaldino, David S.; Arcoria, Paul J.; Bui, Thi-Thien; Pons-Bennaceur, Alexandre; Le, Phuong; Allen, James P.; Ullman, Elijah Z.; Nocilla, Kelsey A.; Zhang, Jing; Perszyk, Riley E.; Kim, Sukhan; Acker, Timothy M.; Taz, Azmain; Burton, Samantha L.; Coe, Kevin; Fritzemeier, Russell G.; Burnashev, Nail; Yuan, Hongjie; Liotta, Dennis C.; Traynelis, Stephen F. (American Chemical Society, 2023-08-11)
    Subunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer’s and Parkinson’s disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(−)-2i, also referred to as (S)-(−)-DQP-997-74, which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC50 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(−)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.