Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

Abstract

The number of N-Methyl-D-aspartate receptor (NMDAR) linked neurodegenerative diseases such as Alzheimer's disease and dementia is constantly increasing. This is partly due to demographic change and presents new challenges to societies. To date, there are no effective treatment options. Current medications are nonselective and can lead to unwanted side effects in patients. A promising therapeutic approach is the targeted inhibition of NMDARs in the brain. NMDARs containing different subunits and splice variants display different physiological properties and play a crucial role in learning and memory, as well as in inflammatory or injury processes. They become overactivated during the course of the disease, leading to nerve cell death. Until now, there has been a lack of understanding of the general functions of the receptor and the mechanism of inhibition, which need to be understood in order to develop inhibitors. Ideal compounds should be highly targeted and even splice-variant-selective. However, a potent and splice-variant-selective NMDAR-targeting drug has yet to be developed. Recently developed 3-benzazepines are promising inhibitors for further drug development. The NMDAR splice variants GluN1-1b-4b carry a 21-amino-acid-long, flexible exon 5. Exon 5 lowers the NMDAR's sensitivity to allosteric modulators by probably acting as an NMDAR modulator itself. The role of exon 5 in NMDAR modulation is still poorly understood. In this review, we summarize the structure and pharmacological relevance of tetrahydro-3-benzazepines.

Keywords: 3-benzazepines; Alzheimer’s disease; GluN2B; ionotropic glutamate receptors; neurodegeneration.

Figure 1

Mechanism of NMDAR overactivation by Aβ (light pink) at the postsynapse (light blue) and the potential decrease in overactivation by 3-benzazepines (dark blue). During stimulus conduction, glutamate (yellow) is released as a neurotransmitter from vesicles (purple) into the synaptic cleft via exocytosis. Glutamate can then activate postsynaptic glutamatergic receptors. Soluble Aβ (light pink) can interact with NMDARs (turquoise), which in turn leads to excitotoxicity due to increased calcium (red) influx, followed by apoptosis induction and neurodegeneration. Figure created partly with Servier Medical Art (Creative Commons Attribution 3.0 Unported License).

Figure 2

The NMDAR structure and the respective inhibitory mechanism are essential for drug development. NMDAR structure with GluN1 (orange) and GluN2 (blue) subunits, formed as a dimer of dimers containing ATD, LBD, and TMD (PDB ID: 6CNA, edited with YASARA structure 20) (A). Relevant and nonrelevant structural modifications for highly selective NMDAR modulators shown via traxoprodil as ifenprodil derivative. The length of the alkyl spacer has a major impact on NMDAR inhibition (green), while the benzylic OH⁻ group was not required for the activity (blue). A hydroxy group on one of the benzenes is a crucial component of an active compound (red). The OH moiety in 4-position of the piperidine ring had no impact on NMDAR activity (pink) (B). Rolling motion of the ATDs and LBDs facilitate the opening and closing of the NMDAR-associated ion channel (C). GluN2B-containing NMDARs are activated by glycine and glutamate (yellow) binding and inhibited by the rolling of LBDs, which is influenced by ATD conformational changes. The rolling motions modify the tension on the TMDs and allow the receptor to open or close. When the LBDs roll down, the tension on the linkers between the LBD and TMD decreases, and the NMDAR eventually closes. Soluble Aβ overactivates the NMDAR, and 3-benzazepine compounds inhibit the NMDAR. The ifenprodil binding pocket is located at the GluN1 (orange) and GluN2B (blue) interface. Further, 3-bezanzepines (green) can inhibit via this NMDAR modulation site. (D,E) Shown is the ifenprodil binding pocket with ifenprodil (D) and (R)-OF-NB1 (E) bound. (R)-OF-NB1 was obtained by introducing the F-atom in the 4-phenylbutyl side chain of WMS-14-10. Aromatic, H-bond, and hydrophobic interactions between the 3-benzazepine and the ifenprodil binding pocket lead to inhibition.

Figure 3

Ifenprodil as a precursor for the synthesis of 3-benzazepine derivatives. All generated 3-benzazepine derivatives were side-chain-modified (N-R2, dark purple) (left). The deconstruction of ifenprodil as a leading compound to the tetrahydro-3-benzazepine to WMS-14-10 and eventually (R)-OF-NB1 (right). Ifenprodil and the tetrahydro-3-benzazepine are constitutional isomers. The methyl moiety and the phenolic and benzylic OH moieties were removed to retrieve WMS-14-10. Adapted from Ritter et al. 2021 [65].