Structure-activity relationship of 39 analogs of laetispicine with antidepressant properties.
The natural product Laetispicine ( N -isobutyl-(3,4-methylendioxyphenyl)-2E, 4E, 9E-undecatrienoamide), was isolated from the Piper laetispicum C. DC and screened, for its antidepressant activity and antinociceptive effects. Structure-functional activities of five natural products indicated that biological activity is dependent on double bonds present within the benzene ring and a conjugated double bond located at positions 2-3 and 4-5 in the molecular structure. To further understand the structural-activity relationship of Laetispicine as a new potent and safe antidepressant, the structural-activity relationship of 39 analogs of Laetispicine were synthetized and tested in forced swimming tests in mice whilst also in protective effects against glutamate or H 2 O 2 induced apoptosis in PC12 cells. The results show that the compound 30 - N -isobutyl-11-(4-chlorophenyl) undeca-2E,4E,9E-trienamide exhibited the same activity as the parental compound Laetispicine, and furthermore, the effective dose of this compound is lower than Laetispicine. Therefore, the compound 30 might be a potentially useful therapy in the treatment of depression. For structure, the conjugated double bonds located at 2-3, 4-5 and isolated double bonds from benzene ring are necessary for the antidepressant activities no matter the different length of carbon chain; the isobutyl connected with acylamino also are necessary; and the benzodioxole moiety is replaceable, the halogen atom in phenyl ring at the para-position could enhance this kind of activity.
School of Pharmacy, Fudan University, Shanghai 201203, China.
Hui
H
Xie
Juan
J
Liu
Min
M
Yu
Yong
Y
Wang
Chunyan
C
Yao
Shuyi
S
Yao
Di
D
Jin
Dingyu
D
Hu
Yanlin
Y
Wang
Jingkang
J
Shen
Shengli
S
Pan
D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents; D017209:Apoptosis / Q000187:drug effects*; D052117:Benzodioxoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003863:Depression / Q000188:drug therapy* / Q000523:psychology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D016716:PC12 Cells / Q000201:enzymology / Q000473:pathology*; D008517:Phytotherapy; D031701:Piper; D051381:Rats; D013315:Stress, Psychological / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013550:Swimming / Q000523:psychology
D000577:Amides; D000928:Antidepressive Agents; D052117:Benzodioxoles; D005231:Fatty Acids, Unsaturated; C512035:N-isobutyl-(3,4-methylenedioxyphenyl)-2,4,9-undecatrienoamide; C000589198:N-isobutyl-11-(4-chlorophenyl)undeca-2,4,9-trienamide; D007770:L-Lactate Dehydrogenase