Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety.
Elisabeth KronenbergFrauke WeberStefanie BruneDirk SchepmannCarmen AlmansaKristina FriedlandErik LauriniSabrina PriclBernhard WünschPublished in: Journal of medicinal chemistry (2019)
σ1 and/or σ2 receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ1 receptor affinity and σ1:σ2 selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ1 affinity ( Ki = 1.9 nM) of this series of compounds. In a Ca2+ influx assay, cis-11b behaved as a σ1 antagonist. cis-11b reveals high selectivity over σ2 and opioid receptors. The interactions of the novel σ1 ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ1 receptor protein. The protonated amino moiety forms a persistent salt bridge with E172. The spiro[benzopyran-1,1'-cyclohexane] scaffold and the cyclohexylmethyl moiety occupy two hydrophobic pockets. Exchange of the N-cyclohexylmethyl moiety by a benzyl group led unexpectedly to potent and selective μ-opioid receptor ligands.
Keyphrases
- chronic pain
- pain management
- binding protein
- papillary thyroid
- magnetic resonance imaging
- squamous cell carcinoma
- high resolution
- high throughput
- ionic liquid
- spinal cord injury
- radiation therapy
- young adults
- mass spectrometry
- capillary electrophoresis
- neoadjuvant chemotherapy
- tissue engineering
- protein protein
- dual energy
- childhood cancer