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 <b>9</b> the thiophene derivative <b>7a</b> was obtained as a bioisostere of the potent GluN2B ligands <i>cis</i>-<b>3</b> and <i>trans</i>-<b>3</b>. [7]Annuleno[<i>b</i>]thiophene <b>8a</b> without a benzylic OH moiety was prepared in a six-step synthesis starting from carboxylic acid <b>18</b>. <b>8a</b> represents a bioisostere of potent GluN2B ligands <b>4</b> and <b>5</b>. [7]Annulenothiophene <b>8a</b> without a benzylic OH moiety reveals approx. 8-fold higher GluN2B affinity (<i>K</i> <sub>i</sub> = 26 nM) than the analogous thiophene derivative <b>7a</b> with a benzylic OH moiety (<i>K</i> <sub>i</sub> = 204 nM). Both thiophene bioisosteres show a slight preference for GluN2B receptors over both σ 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.