Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines

• Regioisomeric spirocyclic furopyridines are synthesized regioselectively.
• The reduced electron density of the pyridine ring is responsible for reduced σ1 affinity.
• The position of the N-atom does not affect the σ1 affinity considerably.
• High selectivity over the σ2 subtype is found.

In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a–d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a–d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a–d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d. In radioligand binding studies the regioisomeric furopyridines 2a–d showed 7- to 12-fold lower σ1 affinity than the benzofuran analog 1. The reduced σ1 affinity of the furopyridines 2a–d is explained with the reduced electron density of the pyridine ring. Since the four regioisomeric furopyridines show almost the same σ1 affinity (Ki = 4.9–10 nM), a directed interaction of the pyridine N-atom with the receptor protein can be excluded.

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