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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, K_i (σ₂ )=200 nM; the highest σ₁ affinity was recorded for the corresponding 2-benzofuran derivative with a CH₂ C=O linker (cis-29, K_i (σ₁ )=129 nM).

SUBMITTER: Bergkemper M

PROVIDER: S-EPMC8048568 | biostudies-literature |

REPOSITORIES: biostudies-literature

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