Abstract
Seventeen tetrahydroisoquinoline derivatives were designed, synthesized and evaluated for inhibition of NO production in lipopolysaccharide-stimulated BV-2 microglial cells. Compounds 5a, 9c and 11a potently attenuated NO production by >60%, and 5a and 11a inhibited BH4 production by >48% at 100 μM. In particular, N-ethylcarbonyl-7-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline (11a) reduced NO production by 64% and tetrahydrobiopterin (BH4) production by 49%. Introducing longer alkyl component at C1 or N2 position led to attenuation of the inhibitory effect. It is possible that 11a inhibits NO production by blocking BH4-dependent dimerization of newly synthesized iNOS monomers.
Original language | English (US) |
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Pages (from-to) | 1160-1170 |
Number of pages | 11 |
Journal | European Journal of Medicinal Chemistry |
Volume | 43 |
Issue number | 6 |
DOIs | |
State | Published - Jun 1 2008 |
Externally published | Yes |
Keywords
- Nitric oxide
- Nitric oxide synthase
- Tetrahydrobiopterin
- Tetrahydroisoquinoline
ASJC Scopus subject areas
- Pharmacology
- Drug Discovery
- Organic Chemistry