Synthesis of σ receptor ligands with a spirocyclic system connected with a tetrahydroisoquinoline moiety via different linkers.

Synthesis of σ receptor ligands with a spirocyclic system connected with a tetrahydroisoquinoline moiety via different linkers.
ChemMedChem. 2020 Dec 17;:
Authors: Wünsch B, Bergkemper M, Schepmann D
Abstract
With the aim to develop new σ 2 receptor ligands, spirocyclic piperidines or cyclohexanamines with 2-benzopyran and 2-benzofuran scaffold were connected with 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-bromoacetaldehyde. The amide linkers were constructed by acylation of amines with chloroacetyl chloride and subsequent nucleophilic substitution, the alkyl linkers were obtained by LiAlH 4 reduction of the corresponding amides. For the development of σ 2 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 σ 1 affinity for the cis -configured cyclohexanamines was found than for the trans -configured derivatives. The highest σ 2 affinity was observed for cis - 31 with a K i value of 200 nM, while the highest σ 1 affinity was recorded for cis - 29 ( K i = 129 nM).
PMID: 33332704 [P...

Source: ChemMedChem - December 17, 2020 Category: Chemistry Authors: Wünsch B, Bergkemper M, Schepmann D Tags: ChemMedChem Source Type: research