(37) Two new sigma-1 leads discovered by scaffold hopping

Objective : “Scaffold-hopping” is a drug design strategy based on the idea that replacing one core scaffold with a structurally related group will maintain pharmacologic activity at a given target. In our search for new ligands for dopamine receptors, we hypothesized that we could “hop” from a linking pyrrolidine group in a set of D4-selective lead compounds to a piperazine group without compromising target binding or selectivity.

Methods: Piperazine analogs of CWC-1-001 (1) and CWC-1-002 (2) were synthesized in a two-step process. First, piperazine was condensed with an aryl isocyanate or acyl chloride to make intermediates 1a and 2a, respectively, and then the N'-amine was alkylated to give final products 1b and 2b. Final compounds were determined to have purity > 95% before submission to the Psychoactive Drug Screening Program (PDSP) to determine binding affinity at diverse neurotransmitter targets.

Results: Compounds 1b and 2b displayed negligible affinity for opioid and serotonergic targets. Like their parent compounds (1 and 2), 1b and 2b had negligible affinity for dopamine D1, D2, and D5 receptors; however, affinities for the D4 receptor were greatly (> 50-fold) diminished, indicating that the D4 receptor is not tolerant to this change in core scaffold. Unexpectedly, both compounds showed low-nM affinity for sigma-1 receptors and high selectivity over sigma-2 receptors (Ki ratio > 700 for 1b, > 800 for 2b).

Conclusions: Though our initial hypothesis that we could "hop" from one core scaffold to another without compromising dopamine D4 receptor binding was not supported, we serendipitously discovered two new lead compounds that have high affinity and selectivity for sigma-1 receptors. Sigma-1 receptor ligands have therapeutic potential as treatments for neuropsychiatric disorders, substance abuse, and pain.