Bidirectional Modification of a Alkaloid Identifies Selective Opioid Ligands.

We report a bidirectional diversification and optimization campaign of the newly identified - and -opioid receptor antagonist GB18, a naturally occurring 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 over . 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 β-arrestin2 recruitment. Third, we advance three leads to (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 and pharmacology, demonstrate GB18 and its analogs as tractable new opioid scaffolds that allow favorable properties to be dialed in and unwanted properties removed.