Synthesis of σ Receptor Ligands with a Spirocyclic System Connected with a Tetrahydroisoquinoline Moiety via Different Linkers

Abstract

With the aim to develop new σ2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2-benzopyran and 2-benzofuran scaffolds were connected to the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety by variable linkers. In addition to flexible alkyl chains, linkers containing an amide as functional group were synthesized. The 2-benzopyran and 2-benzofuran scaffold of the spirocyclic compounds were synthesized from 2-bromobenzaldehyde. The amide linkers were constructed by acylation of amines with chloroacetyl chloride and subsequent nucleophilic substitution, the alkyl linkers were obtained by LiAlH4 reduction of the corresponding amides. For the development of σ2 receptor ligands, the spirocyclic 2-benzopyran scaffold is more favorable than the ring-contracted 2-benzofuran system. Compounds bearing an alkyl chain as linker generally show higher σ affinity than acyl linkers containing an amide as functional group. A higher σ1 affinity for the cis-configured cyclohexanamines than for the trans-configured derivatives was found. The highest σ2 affinity was observed for cis-configured spiro[[2]benzopyran-1,1′-cyclohexan]-4′-amine connected to the tetrahydroisoquinoline system by an ethylene spacer (cis-31, Ki (σ2)=200 nM; the highest σ1 affinity was recorded for the corresponding 2-benzofuran derivative with a CH2C=O linker (cis-29, Ki (σ1)=129 nM).