Synthesis, molecular modeling and SAR study of novel pyrazolo[5,1-f][1,6]naphthyridines as CB2receptor antagonists/inverse agonists.
Pyrazolo[5,1-f][1,6]naphthyridine-carboxamide derivatives were synthesized and evaluated for the affinity at CB1and CB2receptors. Based on the AgOTf and proline-cocatalyzed multicomponent methodology, the ethyl 5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (12) and ethyl 5-(2,4-dichlorophenyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxylate (13) intermediates were synthesized from the appropriate o-alkynylaldehydes, p-toluenesulfonyl hydrazide and ethyl pyruvate. Most of the novel compounds feature a p-tolyl (8a-i) or a 2,4-dichlorophenyl (8j) motif at the C5-position of the tricyclic pyrazolo[5,1-f][1,6]naphthyridine scaffold. Structural variation on the carboxamide moiety at the C2-position includes basic monocyclic, terpenoid and adamantine-based amines. Among these derivatives, compound 8h (N-adamant-1-yl-5-(p-tolyl)pyrazolo[5,1-f][1,6]naphthyridine-2-carboxamide) exhibited the highest CB2receptor affinity (Ki=33nM) and a high degree of selectivity (KiCB1/KiCB2=173:1), whereas a similar trend in the near nM range was seen for the bornyl analogue (compound 8f, Ki=53nM) and the myrtanyl derivative 8j (Ki=67nM). Effects of 8h, 8f and 8j on forskolin-stimulated cAMP levels were determined, showing antagonist/inverse agonist properties for such compounds. Docking studies conducted for these derivatives and the reference antagonist/inverse agonist compound 4 (SR144528) disclosed the specific pattern of interactions probably related to the pyrazolo[5,1-f][1,6]naphthyridine scaffold as CB2inverse agonists.
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/a, 07100 Sassari, Italy.
Antonio
A
Dore
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/a, 07100 Sassari, Italy. Electronic address: asproni@uniss.it.
Battistina
B
Asproni
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/a, 07100 Sassari, Italy.
Alessia
A
Scampuddu
Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara, 17-19, 44121 Ferrara, Italy. Electronic address: gss@unife.it.
Stefania
S
Gessi
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/a, 07100 Sassari, Italy.
Gabriele
G
Murineddu
Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV n. 3, 16132 Genova, Italy.
Elena
E
Cichero
Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV n. 3, 16132 Genova, Italy.
Paola
P
Fossa
Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara, 17-19, 44121 Ferrara, Italy.
Stefania
S
Merighi
Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara, 17-19, 44121 Ferrara, Italy.
Serena
S
Bencivenni
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via F. Muroni 23/a, 07100 Sassari, Italy.
Gérard A
GA
Pinna
D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009287:Naphthyridines; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C000621752:pyrazolo(5,1-f)(1,6)naphthyridine
CB(2) antagonism/inverse agonism; Cannabinoid receptors; Docking studies; Pyrazolo[5,1-f][1,6]naphthyridine