Quinolone bioisosteres of phenolic GluN2B‐selective NMDA receptor antagonists

Abstract

AbstractCyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25‐6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight‐step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel–Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β‐unsaturated ketone 12a. Although the quinolones 13a, 15a, and 16a contain an H‐bond donor group (secondary lactam) as ifenprodil and Ro 25‐6981, they show only moderate GluN2B affinity (Ki > 410 nM). However, the introduction of lipophilic substituents at the quinolone N‐atom resulted in more than 10‐fold increased GluN2B affinity of the benzyl and benzyloxymethyl derivatives cis‐13c (Ko = 36 nM) and 13e (Ko = 27 nM). All compounds are selective over the phencyclidine (PCP) binding site of the N‐methyl‐D‐aspartate (NMDA) receptor. The benzyl derivative 13c showed six‐ and threefold selectivity over σ1 and σ2 receptors, respectively.