Bidirectional modification of a Galbulimima alkaloid identifies selective opioid ligands

We report a bidirectional diversification and optimization campaign of the newly identified mu- and kappa-opioid receptor antagonist GB18, a naturally occurring Galbulimima alkaloid. First, we find that replacement of the GB18 piperidine with pyridine alters the pharmacology from antagonism to partial agonism, with reduced potency but markedly higher receptor selectivity for kappa- over mu-. Second, we optimize this hit via development of a mutually chemoselective cross-coupling of an alkyl iodide/ vinyl triflate pair that leads to a series of low- and sub-nanomolar KOR-selective full agonists, some of which demonstrate bias for G protein activation over βarrestin2 recruitment. Third, we advance three leads to in vivo (mouse) analysis and demonstrate brain penetrance and behavioral effects. In an open-field activity assay, we demonstrate that by increasing G protein signaling preference, agonists display an increase in exploratory, anxiolytic-like behaviors with no signs of sedation. The brevity and success of this campaign, combined with in vitro and in vivo pharmacology, demonstrate GB18 and its analogs as tractable new opioid scaffolds that allow favorable properties to be dialed in and unwanted properties removed.