N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.
In order to detect novel σ receptor ligands, the rigid spiro [[2]benzopyran-1,1′-cyclohexan]-4′-one was connected with amino moieties derived from σ 2 receptor preferring lead compounds resulting in mixtures of transand cis-configured amines 6, 18, and 27. In a four step synthesis the methyl acetals 6 were converted into fluoroethyl derivatives 13 and 30. The most promising σ 2 receptor ligand is the methyl acetal 6a bearing a 2,4-dimethylbenzylamino moiety. The fluoroethyl derivatives 13c and 13d reveal high σ 1 affinity but moderate selectivity over the σ 2 subtype. In mice 13c and 13d showed antiallodynic activity that is stronger than that of the reference σ 1 antagonist BD-1063 (34). Since the antiallodynic activity of 13c could only be partially reversed by the σ 1 agonist PRE-084 (35), it is postulated that a second mechanism contributes to its overall antiallodynic effect. In contrast, the antiallodynic effect of its diastereomer 13d can be totally explained by a σ 1 antagonism.
The influence of an F-atom in the side chain of benzo[7]annulen-7-amines on the affinity towards GluN2B subunit containing NMDA receptors and the selectivity over related receptors was investigated. The synthesis of and was performed by reductive amination of the ketone with primary alkanamines and bearing an F-atom in β-position. The GluN2B affinities of non-fluorinated and fluorinated ligands and are almost identical. The low impact of the F-atom on GluN2B affinity was unexpected, as it influences several chemical and physicochemical properties of the ligands. However, introduction of the F-atom led to reduced selectivity over receptors. Whereas and display still a 2-3-fold preference for GluN2B over receptors, they show almost the same affinity to GluN2B and receptors.
Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.
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