Principals in Programming Languages: Technical Results

This is the companion technical report for ``Principals in Programming Languages'' [20]. See that document for a more readable version of these results. In this paper, we describe two variants of the simply typed $\lambda$-calculus extended with a notion of {\em principal}. The results are languages in which intuitive statements like ``the client must call $\mathtt{open}$ to obtain a file handle'' can be phrased and proven formally. The first language is a two-agent calculus with references and recursive types, while the second language explores the possibility of multiple agents with varying amounts of type information. We use these calculi to give syntactic proofs of some type abstraction results that traditionally require semantic arguments

Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2‑Phenylindole Privileged Structure Scaffold

G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., <b>1</b>–<b>3</b>). Herein, we present the first structure–activity relationship study for the 2-arylindole antagonist <b>3</b>, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP₁) assay we identified compounds <b>7</b>, <b>13e</b>, and <b>34b</b> as antagonists at the GPRC6A receptor in the low micromolar range and show that <b>7</b> and <b>34b</b> display >9-fold selectivity for the GPRC6A receptor over related GPCRs, making <b>7</b> and <b>34b</b> the most potent and selective antagonists for the GPRC6A receptor reported to date