D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline

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Title: D1 dopamine receptor positive allosteric modulators as a practical treatment for cognitive decline Summary: Activation of the D1 dopamine (DA) receptor (D1R) is a promising treatment strategy for the cognitive decline observed in Alzheimer’s disease or other disorders such as schizophrenia and Parkinson’s disease. Work by Goldman-Rakic and colleagues has shown that an optimum level of D1R activity in the prefrontal cortex (PFC) is required for optimum performance in learning and memory. This has led to the inverted-U hypothesis for the relationship of D1R activity in the PFC and cognitive function. At low levels of D1R signaling, such as in diseased states, cognitive function is suboptimum. At extremely high levels of D1R activity, as observed during stress, cognitive function is also at suboptimum levels. D1R agonists have shown promising efficacy in Alzheimer’s disease models for ameliorating cognitive decline, however the clinical liability inherent with orthosteric D1R agonists has limited their therapeutic translation. D1R positive allosteric modulators (PAMs) have the potential for high selectivity, larger therapeutic windows and reduced tolerance. We have identified four structurally distinct hit scaffolds from high-throughput screening (HTS). Preliminary pharmacological characterization has validated these hits as D1R PAM compounds with no measurable D1R agonism on their own. The focus of this proposal is to selectively advance these hit compounds into therapeutic leads. All four HTS hits are structurally distinct from known DA ligands and their D1R PAM activities have been reconfirmed. Two hits (thiophene- and pyrimidone-based compounds) have been further characterized in a wide range of pharmacological studies. Both compounds potentiate DA-stimulated G protein- and -arrestin-mediated signaling and increase the affinity of DA for the D1R. The thiophene hit has proven useful as a chemical tool and allowed us to identify a second D1R allosteric binding site that, to our knowledge, is unique to this scaffold. When tested in combination, maximally effective concentrations of both thiophene- and pyrimidone-based PAMs potentiate DA-stimulated signaling to a greater extent than either PAM alone. These data are difficult to explain without invoking the existence of two D1R allosteric sites that independently mediate the actions of these two different PAMs. Such combination experiments were repeated with Compound B and DETQ, known intracellular loop 2 (ICL2)-binding D1R PAMs that were developed by Bristol-Myers Squibb and Eli Lilly, respectively. Both Compound B and DETQ were additive with the thiophene chemotype, but not with the pyrimidone chemotype, further suggesting that the D1R has at least two separate PAM binding sites. A major focus of our efforts will be to optimize the thiophene hit scaffold that targets a novel and unexplored allosteric site within the D1R to facilitate the development of therapeutic leads. The therapeutic potential for D1R PAMs and the cumulative evidence to date supports further investigation of new scaffolds and the pharmacological characterization of promising lead compounds. Such a systematic approach will provide state-of-the-art tool molecules to investigate D1R allosteric sites as well as advance the therapeutic utility of D1R PAMs.