New combination of pharmacophoric elements of potent sigma(1) ligands: Design, synthesis and sigma receptor affinity of aminoethyl substituted tetrahydrobenzothiophenes

作者：Hare Dipak; Schepmann Dirk; Wuensch Bernhard

来源：European Journal of Medicinal Chemistry, 2013, 69: 490-497.

DOI：10.1016/j.ejmech.2013.09.006

• sigma(1) ligands
• Conformational flexibility
• Combination of pharmacophoric elements
• Tetrahydrobenzothiophenes
• Horner-Wittig reaction

The aminoethyl substituted tetrahydrobenzothiophenes 4 resulted from combination of the pharmacophoric elements of the potent cri ligands 2 and 3. The aminoethyl substituted tetrahydrobenzothiophenes 4 were prepared in an 8-step synthesis starting with thiophene. Whereas the rri affinity of the N-benzyl derivative 4a is in the medium nanomolar range (K-i = 49 nM), the analogous N-cyclohexylmethyl derivative 4d exhibits low nanomolar affinity (Ki = 5.0 nM). The reduced sigma(1) affinity and sigma(2)/sigma(1) selectivity of tetrahydrobenzothiophenes 4 compared to analogous spirocyclic piperidines 3 is attributed to the increased conformational flexibility of the aminoethyl side chain.

• 出版日期2013-11