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Abstract
The synthesis and pharmacological evaluation of analogues of PD 160170, a neuropeptide Y1 (NPY) receptor antagonist are reported. Phamacomodulation of this 8-amino-5-nitro-6-phenylsulfonylquinoline was carried out by replacing the sulfone moiety by oxygen. The corresponding ethers 11 - 16 were obtained by nucleophilic substitution of 8-acetamido-6-chloro-5-nitroquinoline 4 with phenols, followed by acidic hydrolysis of the intermediary amides 5 - 10. The test compounds 11 - 16 exerted no appreciable Y1 activity and they were also inactive in terms of Y5 receptor binding; their IC 50 values were >1 μM and 10 μM, respectively. The dramatic decrease in potency resulting from replacement of the sulfone function by an ether was confirmed by IP administration of 16 to ob / ob mice; after a 4-day administration, no decrease in food consumption or weight was observed.