Synthesis and Structure–Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety

Abstract

σ 1 and/or σ 2 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 σ 1 receptor affinity and σ 1 :σ 2 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 σ 1 affinity (K i = 1.9 nM) of this series of compounds. In a Ca 2+ influx assay, cis-11b behaved as a σ 1 antagonist. cis-11b reveals high selectivity over σ 2 and opioid receptors. The interactions of the novel σ 1 ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ 1 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.

Propellanes as Rigid Scaffolds for the Stereodefined Attachment of σ-Pharmacophoric Structural Elements to Achieve σ Affinity

“…With K i values of 24 nM (σ 1 affinity) and 101 nM (σ 2 affinity), 18 represents the most potent σ ligand of this series of compounds. The increase of both σ 1 and σ 2 affinities by introduction of the cyclohexylmethyl moiety instead of the benzyl moiety has already been observed for some other classes of σ ligands [ 49 , 50 ].…”

“…The starting structure for the σ 1 receptor was obtained from the RCSB Protein Data Bank (PDB ID 5HK1) [ 7 ]. Following a consolidated computational protocol [ 49 , 52 ], the binding modes of compounds 9a ( Figure 10 A,C) and anti - 5 ( Figure 10 B,D) were initially recognized. A MM/PBSA (molecular mechanics/Poisson–Boltzmann surface area) approach [ 53 ] provided the binding free energy (ΔG) of the complexes of both compounds with the σ 1 receptor.…”

Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers

“…and cyclohexanamines 11 [34] and 13 with 2‐benzopyran and 2‐benzofuran scaffold. a) 5 steps; [35] b) 7 steps; [34] c) 4 steps; [36] d) 4 steps; [37,38] e) NH 4 HCO 2 , Pd/C, CH 3 OH, 17–21 h, 65 °C; trans ‐ 13 , 86 %, cis ‐ 13 , 66 %.…”

“…[34]. Transfer hydrogenolysis using NH 4 HCO 2 in the presence of Pd/C converted trans ‐ and cis ‐configured benzylamines trans ‐ 9 and cis ‐ 9 [37,38] into the diastereomeric primary amines trans ‐ 13 and cis ‐ 13 . The secondary amine 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline HCl ( 14 HCl) was commercially available (Scheme 1).…”

“…The synthesis of trans ‐ and cis ‐configured benzylamines trans ‐ 9 and cis ‐ 9 was reported in ref. [37] and [38].…”