Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-d-aspartate receptors

Abstract

N-Methyl-D-aspartate receptors (NMDARs) are known to be involved in a range of neurological and neurodegenerative disorders and consequently the development of compounds that modulate the function of these receptors has been the subject of intense interest. We have recently reported that 6-bromocoumarin-3-carboxylic acid (UBP608) is a negative allosteric modulator with weak selectivity for GluN2A-containing NMDARs. In the present study, a series of commercially available and newly synthesized coumarin derivatives have been evaluated in a structure-activity relationship (SAR) study as modulators of recombinant NMDAR activity. The main conclusions from this SAR study were that substituents as large as iodo were accommodated at the 6-position and that 6,8-dibromo or 6,8-diiodo substitution of the coumarin ring enhanced the inhibitory activity at NMDARs. These coumarin derivatives are therefore excellent starting points for the development of more potent and GluN2 subunit selective inhibitors, which may have application in the treatment of a range of neurological disorders such as neuropathic pain, epilepsy and depression. Surprisingly, 4-methyl substitution of UBP608 to give UBP714, led to conversion of the inhibitory activity of UBP608 into potentiating activity at recombinant GluN1/GluN2 receptors. UBP714 also enhanced NMDAR mediated field EPSPs in the CA1 region of the hippocampus. UBP714 is therefore a novel template for the development of potent and subunit selective NMDAR potentiators that may have therapeutic applicability in the treatment of patients with cognitive deficits or schizophrenia.

Mechanism and properties of positive allosteric modulation of N -methyl- d -aspartate receptors by 6-alkyl 2-naphthoic acid derivatives

“…Alternatively, inhibitory activity could result from UBP684 and UBP753 binding to a second site that is inhibitory whose activity is revealed at alkaline pH. Neurosteroids and compounds structurally-related to UBP684/UBP753 display both NAM and PAM activity at distinct sites and often display greater inhibitory activity at GluN2C and GluN2D as seen here (Costa et al, 2010; Horak et al, 2006; Irvine et al, 2012; Malayev et al, 2002). …”

“…The alkyl-naphthoic acid PAMs characterized here add to the pharmacodynamic diversity of the rapidly expanding list of NMDAR PAMs such as PS (Chopra et al, 2015; Horak et al, 2006; Horak et al, 2004; Jang et al, 2004; Kostakis et al, 2011; Wu et al, 1991), UBP512, UBP646 (Costa et al, 2010), UBP714 (Irvine et al, 2012), CIQ (Mullasseril et al, 2010), PYD106 (Khatri et al, 2014), SGE201 (Linsenbardt et al, 2014; Paul et al, 2013), and GNE6901 (Hackos et al, 2016). These agents differ in their subtype-selectivity, N-terminal insert-sensitivity, pH-sensitivity, use/disuse-dependency, and their effects on agonist potency, efficacy and deactivation.…”

“…Previously we have reported multiple aromatic ring structures substituted with a carboxylic acid group that display NMDAR PAM and/or NAM activity with varied patterns of subunit selectivity (Costa et al, 2012; Costa et al, 2010; Irvine et al, 2012; Irvine et al, 2015). These agents are allosteric modulators interacting at the ligand binding domain (LBD) but they do not compete with either glutamate or glycine binding, nor do they bind at the N -terminal regulatory domain or within the ion channel (Costa et al, 2010).…”

Identification of novel allosteric modulator binding sites in NMDA receptors: A molecular modeling study

“…This is partially because of the lack of knowledge about the full-length NMDAR structure that is comprised of a unique, multi-domain patterns of interaction, which was not elucidated until recently by X-ray crystallography. Our previous studies demonstrate that the compounds are not channel blockers, do not bind at the glutamate or glycine binding sites, and do not require the NTD for their activity [36][37][38]40]. Despite the low affinity exhibited by the modulators at this point, their novelty in activity pattern, chemical structure, and mechanism of action warrant further investigation of their binding site with the aim to contribute for the further development of high affinity compounds.…”

“…Recently, by our ongoing efforts to find out GluN2-selective compounds, we discovered a novel family of allosteric modulators that distinguish between NMDARs depending upon their GluN2 subunit composition [21,[36][37][38][39]. To date, however, the binding site(s) and mechanisms of action of these compounds still remain unknown.…”