Synthesis and resolution of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [(+/-)-PPCC)]: new sigma receptor ligands with neuroprotective effect.
The enantiomers of cis-(+/-)-methyl (1R,2S/1S,2R)-2-[(4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl)cyclopropanecarboxylate [1, (+/-)-PPCC], a selective sigma ligand, were synthesized. The (+)- and (-)-enantiomers bind predominantly to sigma(1) receptors and have a reduced sigma(2) affinity. Both individually restore the astroglial oxidative status modified by glutamate, counteracting also transglutaminase-2 overexpression. They exhibited in vivo anti-opioid effects on kappa opioid (KOP) receptor-mediated analgesia. Our findings demonstrate that the enantiomers display mainly sigma(1) agonist activity and that they have neuroprotective effects.
Prezzavento
Orazio
O
Department of Pharmaceutical Sciences, Medicinal Chemistry Section, University of Catania, Catania, Italy. prezzave@unict.it
Campisi
Agata
A
Parenti
Carmela
C
Ronsisvalle
Simone
S
Aricò
Giuseppina
G
Arena
Emanuela
E
Pistolozzi
Marco
M
Scoto
Giovanna M
GM
Bertucci
Carlo
C
Vanella
Angelo
A
Ronsisvalle
Giuseppe
G
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004347:Drug Interactions; D019204:GTP-Binding Proteins / Q000096:biosynthesis; D018698:Glutamic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D007050:Ibogaine / Q000494:pharmacology; D008024:Ligands; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018384:Oxidative Stress; D010423:Pentazocine / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000096:biosynthesis
D018712:Analgesics, Non-Narcotic; D003521:Cyclopropanes; D008024:Ligands; D018696:Neuroprotective Agents; D010880:Piperidines; D017382:Reactive Oxygen Species; D017473:Receptors, Opioid, kappa; D017480:Receptors, sigma; C000717609:Tgm2 protein, rat; C518986:methyl 2-((4-hydroxy-4-phenylpiperidin-1-yl)methyl)-1-(4-methylphenyl)cyclopropanecarboxylate; D018698:Glutamic Acid; D007050:Ibogaine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins; D005978:Glutathione; D010423:Pentazocine