ABSTRACT
The broad-spectrum antiviral activity of 2-(2-adamantyl)piperidines 11, 13a,b, and 15, 3-(2-adamantyl)pyrrolidines 27, 21a-g and 2-(2-adamantylmethyl)piperidines 30, 32a-c, and 35a-d was examined. Several compounds in the new series were potent against influenza A H(3)N(2) virus. When 1-aminoethyl pharmacophore group of 2-rimantadine 4 (2-isomer of rimantadine) is included into a saturated nitrogen heterocycle, see compound 11, potency was retained. The diamine derivatives 21e-g and particularly 35a-c possessing three pharmocophoric groups, that is, the adamantyl and the two amine groups, exhibited high potency. The new compounds did not afford specific activity at non-toxic concentrations against any of the other viruses tested. According to NMR spectroscopy and molecular mechanics calculations it is striking that the parent structures 11 and 27 adopt a fixed trans conformation around C2-C2' bond. In the parent amines, which proved to be active compounds, the distance between nitrogen and adamantyl pharmacophoric groups was different; N-C2' distance is 3.7, 3.8 A for 27, 30 and 2.5 A for 11 suggesting that M2 receptor site can accommodate different in size and orientation lipophilic cages.
Subject(s)
Adamantane/analogs & derivatives , Antiviral Agents/chemical synthesis , Piperidines/chemical synthesis , Pyrrolidines/chemical synthesis , Adamantane/chemistry , Adamantane/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , HIV/drug effects , Humans , Influenza A Virus, H3N2 Subtype/drug effects , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Piperidines/chemistry , Piperidines/pharmacology , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Viruses/drug effectsABSTRACT
A general synthetic route that can lead to nicotinic ligands bearing a variety of bulky aza-ring systems was developed. This methodology was applied to obtain 5-(3-pyridinyl)- and 5-(3-quinolinyl)-4-azahomoadamantanes 2a, 3a and 2b, 3b. The parent 5-(3-pyridinyl)-4-azahomoadamantane 2a (Ki = 5.0 microM) binds with about 100 times lower affinity than (+)-epibatidine 1 (Ki = 0.045 microM) to alpha7 nicotinic acetylcholine receptors (nAChRs). N-methyl substitution of 2a gives compound 3a which has about nine times lower binding affinity. The replacement of pyridinyl with a quinolinyl ring (compounds 2b, 3b) results in a dramatic reduction in potency (Ki > 1000 microM).
