New quinolone- and 1,8-naphthyridine-3-carboxamides as selective CB2 receptor agonists with anticancer and immuno-modulatory activity.
Several recent studies suggest that selective CB2 receptor agonists may represent a valid pharmacological approach in the treatment of various diseases due to the absence of relevant psychoactive side effect. In this study, we synthesized and tested a series of new quinoline-2(1H)-one- and 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine derivatives characterized by a 4-methylcyclohexylamido substituent in position 3 of the heterocyclic nucleus with high CB2 receptor affinity and selectivity. Two compounds showing the best binding and selectivity profile behaved as a full agonist and a partial agonist at the CB2 receptor and induced a concentration-dependent decrease of cell viability on LNCaP, a prostatic cancer cell line expressing CB2 receptor. Moreover considering that the CB2 receptor is mainly expressed in cells and organs of the immune system, the same compounds were studied for their potential immune-modulatory and anti-inflammatory effects in activated lymphocytes isolated from healthy controls and multiple sclerosis (MS) patients.
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy. Electronic address: manera@farm.unipi.it.
Clementina
C
Manera
Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Anna Maria
AM
Malfitano
University of Eastern Finland, Faculty of Health Sciences, School of Pharmacy, PO Box 1627, 70211 Kuopio, Finland; University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland.
Teija
T
Parkkari
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Valentina
V
Lucchesi
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Sara
S
Carpi
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Stefano
S
Fogli
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Simone
S
Bertini
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II," Napoli.
Chiara
C
Laezza
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
Alessia
A
Ligresti
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Giuseppe
G
Saccomanni
University of Eastern Finland, Faculty of Health Sciences, Institute of Biomedicine, School of Medicine, PO Box 1627, 70211 Kuopio, Finland.
Juha R
JR
Savinainen
Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Elena
E
Ciaglia
Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Simona
S
Pisanti
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Patrizia
P
Gazzerro
Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy.
Vincenzo
V
Di Marzo
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Paola
P
Nieri
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Marco
M
Macchia
Department of Medicine and Surgery, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Salerno, Italy; Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Salerno, Italy.
Maurizio
M
Bifulco
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D012015:Reference Standards
D000577:Amides; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D009287:Naphthyridines; D011804:Quinolines; D043885:Receptor, Cannabinoid, CB2; C037219:quinoline
1,8-Naphthyridine-3-carboxamide; Anticancer activity; Cannabinoid CB2 receptor; Immunomodulation; Multiple sclerosis; Quinoline-3-carboxamide