Discovery and structure–activity relationships of 4-aminoquinazoline derivatives, a novel class of opioid receptor like-1 (ORL1) antagonists

Synthesis and structure–activity relationship studies of a series of 4-aminoquinazoline derivatives led to the identification of (1R,2S)-17, N-[(1R,2S)-2-({2-[(4-chlorophenyl)carbonyl]amino-6-methylquinazolin-4-yl}amino)cyclohexyl]guanidine dihydrochloride, as a highly potent ORL1 antagonist with up to 3000-fold selectivity over the μ, δ, and κ opioid receptors. Molecular modeling clarified the structural factors contributing to the high affinity and selectivity of (1R,2S)-17.

Structure–activity relationships associated with ORL1 antagonists were investigated. (1R,2S)-17 showed highly potent ORL1-antagonist activity and excellent selectivity over the μ, δ and κ opioid receptors.Figure optionsDownload as PowerPoint slide