112396-13-1Relevant articles and documents
Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety
Kronenberg, Elisabeth,Weber, Frauke,Brune, Stefanie,Schepmann, Dirk,Almansa, Carmen,Friedland, Kristina,Laurini, Erik,Pricl, Sabrina,Wünsch, Bernhard
, p. 4204 - 4217 (2019/05/06)
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.
Design, synthesis and pharmacological evaluation of spirocyclic σ1 receptor ligands with exocyclic amino moiety (increased distance 1)
Rack, Elisabeth,Fr?hlich, Roland,Schepmann, Dirk,Wünsch, Bernhard
scheme or table, p. 3141 - 3151 (2011/06/24)
Various pharmacophore models for potent σ1 ligands specify a basic amino group flanked by two different hydrophobic regions in defined distances to the basic amine (distance 1 and distance 2, respectively). According to these models distance 1 of the potent spirocyclic σ1 ligand 1 is too short. In order to find a new class of more potent σ1 ligands and to verify the distance hypothesis of the pharmacophore models spirocyclic compounds 2 with an exocyclic amino group were designed and synthesized. The secondary amines 8 and 9 with N-benzyl residues are >100-fold less potent than the spirocyclic piperidine 1. However, the tertiary methylamines trans-11 and cis-11 represent potent σ1 ligands with Ki-values of 43 and 24 nM, respectively. Whereas one large benzyl moiety is required for high σ1 receptor binding, a second large N-substituent is not tolerated by the σ1 receptor protein. As a rule, cis-configured diastereomers with a longer distance 1 (predominantly 7.16-7.23 ) show higher σ1 affinities than their trans-configured counterparts (distance 1 is predominantly 5.88-6.26 ).
A new method for the preparation of 3-alkoxy- and 3-hydroxy-3,4-dihydro-1H-2-benzopyrans
Wunsch
, p. 493 - 499 (2007/10/02)
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