New combination of pharmacophoric elements of potent σ1 ligands: Design, synthesis and σ receptor affinity of aminoethyl substituted tetrahydrobenzothiophenes

Abstract

The aminoethyl substituted tetrahydrobenzothiophenes 4 resulted from combination of the pharmacophoric elements of the potent σ₁ ligands 2 and 3. The aminoethyl substituted tetrahydrobenzothiophenes 4 were prepared in an 8-step synthesis starting with thiophene. Whereas the σ₁ affinity of the N-benzyl derivative 4a is in the medium nanomolar range (Ki = 49 nM), the analogous N-cyclohexylmethyl derivative 4d exhibits low nanomolar affinity (Ki = 5.0 nM). The reduced σ₁ affinity and σ₂/σ₁ selectivity of tetrahydrobenzothiophenes 4 compared to analogous spirocyclic piperidines 3 is attributed to the increased conformational flexibility of the aminoethyl side chain.