Prior to becoming a graduate student at the University of Michigan, Evan earned a B.S. in Molecular and Cellular Biology from the University of Illinois at Urbana-Champaign in May 2014. At the University of Illinois, he took an undergraduate research position in the lab of Dr. Mary Schuler studying mosquito P450 enzymes capable of metabolizing insecticides making them resistant. As a pharmacology PhD student in the lab of Dr. John Traynor at the University of Michigan, Evan’s research focuses on understanding the function of opioid receptor allosteric modulators engage the and identifying novel modulators compounds with increased potency and efficacy. Opioid receptor allosteric modulators may have therapeutic advantages over traditional opioid drugs used to treat pain.
Role of Probe Dependence and Na+ Ions
in the Allosteric Modulation of the Delta Opioid Receptor
The recent discovery and characterization of positive allosteric modulators (PAMs) targeting the mu and delta opioid receptors (MOPr and DOPr, respectively) has provided us with a potential new pharmacological approach for the treatment of pain and mood disorders. Allosteric modulators bind to a site on the receptor that is spatially distinct from the orthosteric site for endogenous ligands where they influence the binding affinity and signaling profile of orthosteric ligands. BMS-986122 is a PAM for MOPr that functions by counteracting the inhibitory effect of Na+ ions on receptor activation. BMS-986187 is a recently identified PAM for DOPr that is structurally dissimilar from BMS-986122. To examine if the mode of allosteric modulation at MOPr and DOPr by these diverse compounds is the same, we examined the probe dependence and role of Na+ ions in the allosteric modulation of DOPr by BMS-986187. Radioligand competition binding assays with membranes from CHO-hDOPr cells were performed for a variety of orthosteric ligands in both the presence or absence of 100mM NaCl or BMS-986187. GTPγ35S binding in membranes was used to examine the influence of BMS-986187 on receptor activation. There was profound probe dependence to the action of BMS-986187, for example, the affinity of the peptidic DOPr agonist shifted 59-fold-whereas the potency of the small molecule agonist BW373U86 was only marginally affected. This probe dependence was seen to be due to an allosteric antagonism between Na+ ions and BMS-986187, confirming the same mode of action as allosteric modulation at MOPr. Supported by R01 DA033396 and T32 GM008597.