Targeting a2R/TMEM97 with novel aminotetralins

Initially associated with cancer diagnosis and therapy, the sigma 2 receptor (a2R) has recently been implicated in several disorders of the central nervous system (CNS). It remained a poorly characterized target until we identified it as the transmembrane protein 97 (TMEM97). As part of a program to identify novel compounds that bind with high affinity and selectivity to a2R/TMEM97 relative to the sigma 1 receptor (a1R) and other CNS proteins, we employed a scaffold simplification strategy to design novel sets of piperazine-substituted aminotetralins based on analogous norbenzomorphans that we previously developed. JVW-1601 was iden-tified as a reference aminotetralin analog that had high affinity (Ki= 5.5 nM) and selectivity (36-fold) for a2R/TMEM97 versus a1R. An expanded investigation of structure-activity relationships (SAR) in several structural regions of this compound was conducted, and among the ligands thus prepared, many had Ki values < 20 nM for a2R/TMEM97 and selectivities of > 20-fold versus a1R. Structural features that enhance a2R/TMEM97 affinity and selectivity were identified, leading to an optimized compound having a high a2R/TMEM97 affinity (Ki of 4.5 nM) and 366-fold selectivity relative to a1R. Significantly, during the course of this work we discovered JVW-1625, which enabled the isolation and identification of a2R as TMEM97 and resolved a question that had eluded researchers for decades. Computational docking studies for selected aminotetralins suggest they adopt similar poses upon binding to a2R/TMEM97, engaging in highly conserved salt bridges with Asp29 and cation-a interactions with Tyr150. Collectively, these studies show that aminotetralins are useful tool compounds for studying the mechanism and function of a2R/TMEM97.