Replacement of the Benzylpiperidine Moiety with Fluorinated Phenylalkyl Side Chains for the Development of GluN2B Receptor Ligands

Abstract

The 4‐benzylpiperidine moiety is a central structural element of potent N‐methyl‐d‐aspartate (NMDA) receptor antagonists containing the GluN2B subunit. To obtain novel GluN2B ligands suitable for positron emission tomography, the benzylpiperidine moiety was replaced with fluorinated ω‐phenylalkylamino groups. For this purpose three primary propyl‐ and butylamines 7 a–c and one butyraldehyde 7 d bearing a fluorine atom and an ω‐phenyl moiety were prepared in 3‐ to 7‐step syntheses. Compounds 7 a–d were attached to various scaffolds of potent GluN2B antagonists (scaffold hopping) instead of the original 4‐benzylpiperidine moiety. Although benzoxazol‐2‐ones and indoles with a benzylpiperidine moiety show high GluN2B affinity, the corresponding fluorophenylalkylamine derivatives did not result in high Glu2B affinity. Moderate GluN2B affinity was observed for a 3‐(fluoroalkyl)‐substituted tetrahydro‐1H‐3‐benzazepine (Ki=239 nm). However, high GluN2B affinity was obtained for the tetrahydro‐5H‐benzo[7]annulen‐7‐amines 12 a–c (Ki=17–30 nm). Docking studies resulted in the same binding pose for 12 a as for the lead compound Ro 25‐6981. It can be concluded that some GluN2B ligands (benzoxazolones, indoles) do not tolerate replacement of the 4‐benzylpiperidine moiety with flexible fluorinated phenylalkyl side chains, but other scaffolds such as tetrahydro‐3‐benzazepines and ‐benzo[7]annulenes retain interaction with NMDA receptors containing the GluN2B subunit.

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

“…101,606 (Chenard et al, 1995), radiprodil (Mullier et al, 2017), Merck-20j, andMK-0657 (Liverton et al, 2007;Addy et al, 2009) (Table 10). Alternative scaffolds include propanolamines (Tahirovic et al, 2008), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Claiborne et al, 2003;McIntyre et al, 2009;Mosley et al, 2009;Brown et al, 2011;Beinat et al, 2014;Buemi et al, 2014;Bristow et al, 2017;Dey et al, 2018;Thum et al, 2018;Zscherp et al, 2018;Zampieri et al, 2019;Zhang et al, 2019). Molecules with two aromatic rings separated by a linker also cross over to act selectively on GluN2B, including the dopamine receptor antagonist haloperidol, the r and dopamine receptor antagonist trifluperidol, the H 3 histamine receptor antagonists clobenpropit and iodophenpropit, the b-adrenergic receptor agonist nylidrin, and the TRPV1 receptor antagonist capsazepine (Supplemental Table 13).…”

A Glutamate N-Methyl-d-Aspartate (NMDA) Receptor Subunit 2B–Selective Inhibitor of NMDA Receptor Function with Enhanced Potency at Acidic pH and Oral Bioavailability for Clinical Use

“…Since the discovery of GluN2B-selective antagonists, numerous scaffolds of highly selective GluN2B NMDA receptor antagonists have been reported (reviewed by Layton et al, 2006;Mony et al, 2009;Koller and Urwyler, 2010;Ruppa et al, 2012). These include phenethanolamines such as ifenprodil (Williams, 1993), eliprodil (Carter et al, 1988), radiprodil (Michel et al, 2014;Auvin et al, 2020), traxoprodil (Chenard et al, 1995), Ro 25-6981 (Fischer et al, 1997), MK-0657 (Addy et al, 2009), plus additional scaffolds including propanolamines (Yuan et al, 2015), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Mosley et al, 2009;McIntyre et al, 2009;Brown et al, 2011;Buemi et al, 2014;Dey et al, 2018;Thum et al, 2018). Whereas crystallographic evaluation of ifenprodil at the GluN1/GluN2B heterodimer amino terminal domain (ATD) interface (Karakas et al, 2014) is the likely pose for many GluN2B-selective inhibitors, recent structural data revealed a unique region within the binding cavity that can be occupied by compounds with a more compact scaffold (Kemp and Tasker, 2009;Stroebel et al, 2016).…”

Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

“…Ketones 5a‐f with different substituents in 2‐position were reductively aminated at 7‐position with various primary amines 6a‐e to obtain the desired secondary amines 9c,e , 10a‐c,e , 11d , 12a‐c , 13c , and 14a (Scheme ). The syntheses of fluorinated phenylpropylamine 6a as well as in β‐ and γ‐position fluorinated phenylbutylamines 6b and 6c have already been reported . To evaluate the effect of the F‐atom in the phenylalkyl side chain on the GluN2B affinity and selectivity over related receptors, nonfluorinated analogues were also synthesized by reductive amination of ketones 5a‐f with phenylpropyl‐ and phenylbutylamine 6d and 6e , respectively.…”

“…In a previous study, we have shown that an F‐atom in the side chain of benzo[7]annulen‐7‐amines is well tolerated by GluN2B subunit containing NMDARs . Furthermore, a scaffold hopping approach led to the result that benzo[7]annulene derivatives are in combination with fluorinated phenylalkyl side chains superior to other scaffolds …”

“…Various substituents in 2‐position were considered; the secondary amine should be transformed into different tertiary amines, and the fluorine atom should be introduced on either β‐ or γ‐position of the phenylpropyl or phenylbutyl side chain. For the synthesis of the designed ligands 4 , ketones 5 with different substituents in 2‐position should be synthesized and combined via reductive amination with phenylalkylamines 6a‐c fluorinated in β‐ or γ‐position . Further variations in 2‐position and at the amino group are envisaged to obtain a diverse set of benzo[7]annulen‐7‐amines 4 (Figure ).…”