Syntheses of tetrahydroisoquinoline derivatives that inhibit NO production in activated BV-2 microglial cells.
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 microM. 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.
Seo
Jai Woong
JW
Department of Chemistry, Inha University, 253 Yonghyundong Namgu, Inchon 402-751, Republic of Korea.
Srisook
Ekaruth
E
Son
Hyo Jin
HJ
Hwang
Onyou
O
Cha
Young-Nam
YN
Chi
Dae Yoon
DY
D000818:Animals; D002460:Cell Line; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D021241:Spectrometry, Mass, Electrospray Ionization; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D044005:Tetrahydroisoquinolines; D009569:Nitric Oxide