An NMDAR positive and negative allosteric modulator series share a binding site and are interconverted by methyl groups

N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency. Data suggest that these modulators, including both enantiomers, bind to the same site on the receptor and share structural determinants of action. Due to the modulator properties, submaximal negative modulators in this series may spare NMDAR at the synapse, while augmenting the response of NMDAR in extrasynaptic spaces. These modulators could serve as useful tools to probe the role of extrasynaptic NMDARs.

Ultimate and Proximal Determinants of Motivation Given an Attribution Perspective and the Metaphors Guiding Attribution Theory

Attribution theory includes mastery and maintenance of society among its ultimate determinants of action and a variety of information sources and emotions as the proximal or immediate determinants of motivation. These goals are guided by two metaphors: the person as a scientist and the person as a judge. I discuss these positions and point out some of the perceived limitations of the articles in this special issue.