Novel sigma receptor ligands. Part 2. SAR of spiro[[2]benzopyran-1,4'-piperidines] and spiro[[2]benzofuran-1,4'-piperidines] with carbon substituents in position 3.
Several spiro[[2]benzopyran-1,4'-piperidines] and spiro[[2]benzofuran-1,4'-piperidines] were synthesized and evaluated for their binding properties for sigma(1) and sigma(2) receptors. The key step for the introduction of a one carbon residue is the reaction of the cyclic methyl acetals 2a and 3a with trimethylsilyl cyanide to yield the nitriles 5 and 20. The reaction of the lactols 2b and 3b with stabilized phosphoranes affords spiropiperidines with a two carbon residue in position 3. In agreement with previously reported sigma(1) and sigma(2) receptor binding data, the investigated spiro compounds display higher affinity for sigma(1) vs sigma(2) receptors. Compounds with a cyano group in position 3 of the spirocycle show high sigma(1) receptor affinity and selectivity. The spirobenzopyran nitrile 5 and the homologous spirobenzofuran nitriles 20 and 23 show almost identical sigma(1) affinities, whereas the spirobenzopyran nitrile 13 with a methylene spacer is 10-fold less potent. Among the reported compounds, 1'-benzyl-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine]-3-carbonitrile 5 represents the most potent sigma(1) receptor ligand with a K(i) value of 1.54 nM and a sigma(1)/sigma(2) selectivity ratio of 1030.
Maier
Christoph A
CA
Pharmazeutisches Institut der Universität Freiburg, Albertstrasse 25, D-79104 Freiburg i. Br., Germany.
Wünsch
Bernhard
B
D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C467716:1'-benzyl-3,4-dihydrospiro((2)benzopyran-1,4'-piperidine)-3-carbonitrile; D001578:Benzopyrans; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma; D013141:Spiro Compounds