Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

• MeSH
• aminochinoliny chemická syntéza   farmakologie   MeSH
• Caco-2 buňky MeSH
• enzymatické testy MeSH
• histidin chemie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• skot MeSH
• synthasa oxidu dusnatého, typ I antagonisté a inhibitory   chemie   MeSH
• synthasa oxidu dusnatého, typ II antagonisté a inhibitory   MeSH
• synthasa oxidu dusnatého, typ III antagonisté a inhibitory   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• myši MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH