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

• Pharmacophoric elements of different compounds were combined.
• Benzothiophenes with a flexible aminoethyl side chain were prepared.
• The most potent compound showed low nanomolar σ1 affinity.
• Relationships between the structure and the σ1 affinity were elaborated.

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.

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