Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. Phytochemistry. 2021 Mar;183:112598. doi: 10.1016/j.phytochem.2020.112598.
Epub  2020 Dec 25.

Biotransformation of papaverine and in silico docking studies of the metabolites 
on human phosphodiesterase 10a.

Eliwa D(1), Albadry MA(2), Ibrahim AS(3), Kabbash A(3), Meepagala K(4), Khan 
IA(5), El-Aasr M(3), Ross SA(6).

Author information:
(1)National Center for Natural Products Research, School of Pharmacy, The 
University of Mississippi, MS, 38677, USA; Department of Pharmacognosy, Faculty 
of Pharmacy, Tanta University, Tanta, 31527, Egypt.
(2)National Center for Natural Products Research, School of Pharmacy, The 
University of Mississippi, MS, 38677, USA.
(3)Department of Pharmacognosy, Faculty of Pharmacy, Tanta University, Tanta, 
31527, Egypt.
(4)USDA-ARS, Natural Products Utilization Research Unit, University, MS, USA.
(5)National Center for Natural Products Research, School of Pharmacy, The 
University of Mississippi, MS, 38677, USA; Division of Pharmacognosy, Department 
of Biomolecular Sciences, School of Pharmacy, University of Mississippi, MS, 
38677, USA.
(6)National Center for Natural Products Research, School of Pharmacy, The 
University of Mississippi, MS, 38677, USA; Division of Pharmacognosy, Department 
of Biomolecular Sciences, School of Pharmacy, University of Mississippi, MS, 
38677, USA. Electronic address: sross@olemiss.edu.

The metabolism of papaverine, the opium benzylisoquinoline alkaloid, with 
Aspergillus niger NRRL 322, Beauveria bassiana NRRL 22864, Cunninghamella 
echinulate ATCC 18968 and Cunninghamella echinulate ATCC 1382 has resulted in 
O-demethylation, O-methylglucosylation and N-oxidation products. Two new 
metabolites (4″-O-methyl-β-D-glucopyranosyl) 4'-demethyl papaverine and 
(4″-O-methyl-β-D-glucopyranosyl) 6-demethyl papaverine, (Metabolites 5 and 6) 
together with 4'-O-demethylated papaverine (Metabolite 1), 3'-O-demethylated 
papaverine (Metabolite 2), 6-O-demethylated papaverine (Metabolite 3) and 
papaverine N-oxide (Metabolite 4) were isolated. The structure elucidation of 
the metabolites was based primarily on 1D, 2D-NMR analyses and HRMS. These 
metabolism results were consistent with the previous plant cell transformation 
studies on papaverine and isopapaverine and the microbial metabolism of 
papaveraldine. In silico docking studies of the metabolites using crystals of 
human phosphodiesterase 10a (hPDE10a) revealed that compounds 4, 1, 6, 3, and 5 
possess better docking scores and binding poses with favorable interactions than 
the native ligand papaverine.

Copyright © 2020 Elsevier Ltd. All rights reserved.

DOI: 10.1016/j.phytochem.2020.112598
PMID: 33360527 [Indexed for MEDLINE]


2. Molecules. 2010 Feb 23;15(2):988-96. doi: 10.3390/molecules15020988.

Synthesis, cytotoxic and antimalarial activities of benzoyl thiosemicarbazone 
analogs of isoquinoline and related compounds.

Pingaew R(1), Prachayasittikul S, Ruchirawat S.

Author information:
(1)Department of Chemistry, Faculty of Science, Srinakharinwirot University, 
Sukhumvit 23, Bangkok 10110, Thailand. ratchanok@swu.ac.th

Thiosemicarbazone analogs of papaveraldine and related compounds 1-6 were 
synthesized and evaluated for cytotoxic and antimalarial activities. The 
cytotoxic activity was tested against HuCCA-1, HepG2, A549 and MOLT-3 human 
cancer cell lines. Thiosemicarbazones 1-5 displayed cytotoxicity toward all the 
tested cell lines, while compounds 2-5 selectively showed potent activity 
against the MOLT-3 cell lines. Significantly, N(4)-phenyl-2-benzoylpyridine 
thiosemicarbazone 4 exhibited the most potent activity against HuCCA-1, HepG2, 
A549 and MOLT-3 cell lines with IC50 values of 0.03, 4.75, 0.04 and 0.004 
microg/mL, respectively. In addition, 2-benzoylpyridine thio-semicarbazones 3 
and 4 showed antimalarial activity against Plasmodium falciparum with IC50 of 
10-7 to < 10-6 M. The study demonstrates the quite promising activity of analog 
4 as a lead molecule for further development.

DOI: 10.3390/molecules15020988
PMCID: PMC6263187
PMID: 20335957 [Indexed for MEDLINE]


3. J Pharm Biomed Anal. 2006 Jun 16;41(4):1391-5. doi:
10.1016/j.jpba.2006.02.036.  Epub 2006 Mar 31.

Kinetics of photooxidation of papaverine hydrochloride and its major 
photooxidation products.

Piotrowska K(1), Hermann TW, Augustyniak W.

Author information:
(1)Department of Physical Pharmacy and Pharmacokinetics, Poznań University of 
Madical Sciences, 6 Swiecickiego Street, 60-781 Poznań, Poland.

HPCE methodology was modified to be used in kinetic experiments on 
photooxidation reactions of papaverine hydrochloride 1 and its oxidation 
products (papaverinol 2 and papaveraldine hydrochloride 3) chloroform solutions 
exposed to UV254 light in aerobic conditions. On photooxygenation of the above 
compounds is formed the final degradation product, a brown compound X 4, 
2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinylim chloride. The rate 
of 4 formation from the above compounds can be given as 2>3>1>1 HCl. The 
photooxidation reactions of 1 and 2 proceed with pseudo first-order kinetics and 
that reaction for 3 follows zero-order kinetics. The most labile compound is 2 
whose half-life time is 2.4 times shorter than that one of 1 HCL. The most 
stable product is 3 whose half-life time is 31-fold longer than of 2. The 
specific quantum yields are equal 0.28, 0.30 and 0.10 for 1 HCl, 2 and 3, 
respectively which confirm the above stability pattern of the compounds 
concerned.

DOI: 10.1016/j.jpba.2006.02.036
PMID: 16580169 [Indexed for MEDLINE]


4. Arch Pharm (Weinheim). 2003 Sep;336(9):401-5. doi: 10.1002/ardp.200300751.

Oxidation and degradation products of papaverine. Part II[1]: investigations on 
the photochemical degradation of papaverine solutions.

Girreser U(1), Hermann TW, Piotrowska K.

Author information:
(1)Department of Pharmaceutical Chemistry, Christian-Albrechts-University, Kiel, 
Germany. girreser@pharmazie.uni-kiel.de

The structure of the final degradation product formed in papaverine solutions in 
either water or chloroform was found to be a 2, 3, 9, 
10-tetramethoxy-12-oxo-12H-indolo [2, 1-a] isoquinolinylium salt (a dibenzo [b, 
g] pyrrocolonium derivative). Its formation from papaverine oxidation products 
that is papaverinol, papaveraldine, and papaverine-N-oxide chloroform solutions 
under the influence of UV light, was investigated and possible reaction pathways 
are discussed.

DOI: 10.1002/ardp.200300751
PMID: 14528487 [Indexed for MEDLINE]


5. Acta Pol Pharm. 2002 Sep-Oct;59(5):359-64.

Photooxidation of papaverine, papaverinol and papaveraldine in their chloroform 
solutions.

Piotrowska K(1), Hermann TW, Augustyniak W.

Author information:
(1)Department of Physical Chemistry, K. Marcinkowski University of Medical 
Sciences, 6 Swiecickiego Str., 60-781 Poznań, Poland.

Papaverine hydrochloride, papaverinol, and papaveraldine chloroform solutions 
were exposed to UV light of 254 nm in atmospheric, aerobic and anaerobic 
(helium) conditions. The same degradation products appear (TLC) in the above 
papaverine hydrochloride chloroform solutions. However, the rate of papaverine 
hydrochloride degradation processes is enhanced as a function of oxygen 
pressure. Papaverinol and papaveraldine photooxidation products are essentially 
not different from those observed in the above papaverine hydrochloride 
solutions. However, the amount of an unknown brown degradation product (X) is 
the greatest in the papaverinol chloroform solution degraded. That brown 
compound was previously observed in papaverine either hydrochloride or sulfate 
injection solutions on their storage even when protected from daylight. The 
preliminary X product structure development was undertaken (TLC, molecular 
weight, elemental analysis, UV/VIS, IR and 13C MAS NMR spectroscopy).

PMID: 12602797 [Indexed for MEDLINE]