On the basis of docking studies carried out using the recently published cannabinoid receptor models,(35) new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a K-i of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl) quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with K-i of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (K-i(CB1)/K-i(CB2) ratio greater than 303). Moreover, the [S-35]GTP gamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.

Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists

CASTELLI, MARIA PAOLA;
2006-01-01

Abstract

On the basis of docking studies carried out using the recently published cannabinoid receptor models,(35) new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives were designed, synthesized, and tested for their affinities toward the cannabinoid CB1 and CB2 receptors. Compound 10, which presented p-fluorobenzyl and carboxycycloheptylamide substituents bound in the 1 and 3 positions of the 1,8-naphthyiridine-4-one nucleus, showed a high CB2 affinity with a K-i of 1.0 nM. The substitution of the naphthyridine-4-one nucleus with the quinoline-4-one system determined a general increase in CB2 affinity. In particular, the N-cyclohexyl-7-chloro-1-(2-morpholin-4-ylethyl) quinolin-4(1H)-on-3-carboxamide (40) possessed a remarkable affinity, with K-i of 3.3 nM, which was also accompanied by a high selectivity for the CB2 receptor (K-i(CB1)/K-i(CB2) ratio greater than 303). Moreover, the [S-35]GTP gamma binding assay and functional studies on human basophils indicated that the 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives behaved as CB1 and CB2 receptor agonists.
2006
BRAIN CANNABINOID RECEPTOR; PIG MAST-CELLS; RAT-BRAIN; PHARMACOLOGICAL CHARACTERIZATION; IMMUNOLOGICAL ACTIVATION
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11584/17183
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 69
  • ???jsp.display-item.citation.isi??? 61
social impact