Synthesis and receptor binding of thiophene bioisosteres of potent GluN2B ligands with a benzo[7]annulene-scaffold

The involvement of NMDA receptors containing the GluN2B subunit in neurodegenerative disorders including Alzheimer's and Parkinson's disease renders this NMDA receptor subtype an interesting pharmacological target. The aim of this study was the bioisosteric replacement of benzene, methoxybenzene and aniline moieties of known potent GluN2B selective NMDA receptor antagonists by a thiophene ring. In a nine-step synthesis starting from commercially available propionic acid 9 the thiophene derivative 7a was obtained as a bioisostere of the potent GluN2B ligands cis-3 and trans-3. [7] Annuleno.b] thiophene 8a without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid 18. 8a represents a bioisostere of potent GluN2B ligands 4 and 5. [7] Annulenothiophene 8a without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (Ki = 26 nM) than the analogous thiophene derivative 7a with a benzylic OH moiety (Ki = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both s receptors. The data indicate that the bioisosteric replacement of benzene or substituted benzene rings by a thiophene ring is well tolerated by the NMDA receptor. Furthermore, the benzylic OH moiety seems not to be essential for high GluN2B affinity.