“SYNTHESIS AND EVALUATION OF IFENPRODIL
ANALOGUES FOR THEIR PHARMACOLOGICAL
ACTIVITY”
M.PHARM DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
BY,
PATEL VIJAYKUMAR AMRUTLAL
B. Pharm.,
UNDER THE GUIDANCE OF
Dr. B. RAMESH
M.Pharm., Ph.D.,
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
SAC COLLEGE OF PHARMACY
B.G.NAGARA
KARNATAKA -571448
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE-II
1
Name of
Address
the
candidate
& PATEL VIJAYKUMAR AMRUTLAL
S. A. C. COLLEGE OF PHARMACY
B.G.NAGARA, NAGAMANGALA (TALUK)
MANDYA (DIST)-571448, KARNATAKA
PERMANENT ADDRESS:
B/H BHAGWATI SOCIETY, STREET NO.-4
BECHARPURA, TALUKA –PALANPUR, DIST –
BANASKANTHA,
PIN.
NO-385001
,STATEGUJARAT
2
Name of the institute
SAC COLLEGE OF PHARMACY
B.G.NAGARA, KARNATAKA -571448
3
Course of the study
M. PHARM IN PHARMACEUTICAL CHEMISTRY,
4
Date of admission
13/05/2010
5
Title of the topic
“SYNTHESIS AND EVIOLUTION OF
IFENPRODILANALOGUES FOR THEIR
PHARMACOLOGICAL ACTIVITY.”
2
ENCLOSURE-I
6. BRIEF RESUME OF INTENDED WORK:
6.1 NEED FOR STUDY:
The evidence supporting a role of excessive glutamate release or receptor activation in
pathological processes of central nervous system led to the development of two prototypic
NR2B subtype-selective antagonists, ifenprodil and its analogue Ro25-6981 as
neuroprotective agents and to bind ifenprodil site. The following features having the impact
on pharmacological effect (1) benzene-fused ring substitution and modification(R and Y);
(2) the nature of X spacer; (3) the presence of another positive ionizable group(z)on the
benzylpiperidine moiety. The N- methyl-D-aspartate (NMDA) receptor associated ligand
gated ion channel controlling the flow of Ca+2, Na+2, and K+ ions plays a central role in
physiological processes. The NMDA receptor exists as tetrameric subunit such as NR1 and
NR2 (NR2A-D). NR2B subtype selective antagonists inhibit NMDA receptor function by a
non-competitive allosteric mechanism e.g. ifenprodil because competitive NMDA
antagonists exhibits a more side-effect. Overactivation of the NMDA receptor caused
neuronal damage and at the end cell death. Due to its central role in these processes the
NMDA receptor subtype represents an interesting target for the development of drugs that
retaining a therapeutic efficacy but exhibiting a reduced side-effect.1-4, 8-10
Introduction of a hydrophobic substituent into the R2-position of benzimidazoles,
maintained receptor affinity.5
Several compounds, including (+) benzomorphans and more simplified structures
containing substituted piperidine or piperazine, have been reported to bind at σ1 receptor
with high affinity.6
The high electonegativity and the small size of the fluorine atom as well as its different
chemical reactivity with respect to a proton, hydroxyl or carbonyl moiety will affect the
pharmacodynamic as well as the pharmacokinetic properties of pharmacological active
compounds.7
A number of lines of evidence suggested that NR2B subtype-selective blockade of NMDA
receptor can be beneficial, in cerebral ischemia, epilepsy, parkinson’s disease, depression
& perhaps Alzheimer’s disease.11
3
This letter describes the stepwise approach toward thiol-reactive ifenprodil derivatives
suitable for structural investigations of the binding site for NR2B selective inhibitors of the
NMDARs.12
Cardiovascular diseases are the main cause of death in most countries. One of the main
reasons in cardiovascular diseases is involvement of vascular tissues through increasing
tonicity or losing their capacity to relaxation. Vasodilators are the drugs which dilate the
blood vessels and increase the output of blood flow. The drugs acting on blood vessels may
increase the lumen of blood vessels by relaxing the vascular muscles.13, 14
Herewith, we planned to synthesize novel ifenprodil analogs. The novel substituted
ifenprodil analogs will be screened for their pharmacological activity.
6.2. REVIEW OF LITERATURE:
Rosaria G, et al.,1 have reported development of 3-substituted-1H-indole derivatives that
showed NR2B binding affinity equipotent to that of ifenprodil.
Bastian T, et al.,2 have reported synthesis and biological evaluation of tetrahydro-3benzazepine-1,7-diols that showed excellent selectivity, antagonizes glutamate induced
excitotoxicity and is metabolically more stable than ifenprodil and shows analgesic
activity.
Gaelle R, et al.,3 have reported synthesis, radiosynthesis and in vivo evaluation of 5-[3-(4benzylpiperidin-1-yl)prop-1,3-dihydrobenzoimidazol-2-[11C]one that competition studies
with ifenprodil failed to demonstrate specific binding to the radiotracer in the brain by
using PET.
Ahmed EH, et al.,4 have reported and propose that the binding geometry of the sulfonic
moiety within the NMDA receptor is different from that of the phosphonic containing
antagonists.
Takeshi F, et al.,5 have reported synthesis and biological evaluation of radio-iodinated
benzimidazole derivatives was too low to allow for in vivo SPET imaging.
Francesco B, et al.,6 have reported N-[ω-(indan-1-yl and tetralin-1-yl)alkyl] derivatives of
3,3-dimethylpiperidine showed high σ1 affinity assayed (+)-[3H]-pentazocine on guinea-pig
brain and EBP sites.
Ashutosh B, et al.,7 have reported a series of dioxadrol analogues with fluorine substituents
showed high selectivity against σ1 and σ2 receptors as well as the polyamine binding site
of NR2B receptors.
4
Thomas P, et al.,8 have reported derivative of 5-(4-aminobutyl)-2-thiophene-octylamine,a
potent polyamine-sensitive inhibitor of the NMDA receptor and evaluated as inhibitors of
[3H]MK-80] binding to rat brain membranes.
Erik A, et al.,9 have reported synthesis of N-[11C]-(2-methoxy)benzyl(E)-styrene-,2naphthyl-& 4-trifluoromethoxyphenyamidine and evaluated as PET ligands.
Amir PT, et al.,10 have reported a series of 2-substituted 1,2,3,4-tetrahydro-9H-pyrido[3,4b]indoles was synthesized as potential antagonists and assayed by electrical recording
under steady-state conditions.
Cara AM, et al.,11 have reported synthesis, structural activity-relationship, and biological
evaluation of novel amide-based that decrease undesirable side effects and maintaining ontarget potency.
Karine A, et al.,12 have reported to prepare thiol-reactive ifenprodil derivatives designed as
potential probes for cysteine-substituted NR2B containing NMDA receptor.
Xiaowu D, et al.,13 have reported synthesis and evaluation of prenylated flavonoids as
vasorelaxant agents by using support vector machine(SVM).
Sathish NK, et al.,14 have reported vasodilator activity of 4-(4-benzylidenepiperidin-1-yl)1-(4-fluorophenyl)butan-1-ol.
6.3. OBJECTIVES:
1.
Synthesis of different substituted Ifenprodil analogues.
2.
The compounds will be purified by recrystallization using suitable solvents,
TLC, Column Chromatography, etc.
3.
Newly synthesized analogues will be characterized by UV, IR, NMR, MASS
Spectral techniques.
4.
The newly synthesized analogues will be evaluated for their Pharmacological
activity.
5
ENCLOSURE: II
7. .METHODOLOGY
Scheme: - Substituted benzyl piperidines are treated with different alkyl substituted phenyl
rings.
X
N
R1
(CH 2)n
OH
R1=R2=F,Cl,Br, etc.
n= 2,3,etc.
X=C,N
R2
PHARMACOLOGICAL ACTIVITY:
1- Vasodilator activity by estimating the output of blood flow in the blood vessel.14
2- Anticonvulsant activity by MES test.15
3- Antioxidant activity by pyrogallol autooxidation inhibition.15
7.1 SOURCE OF DATA:
The literature survey will be done by referring chemical abstracts of all the national and
international journals pertaining to synthetic, medicinal and pharmaceutical chemistry.
The information about pharmacological and biological activities will be collected by
referring Indian Journals of Medicinal Chemistry, Current Medicinal Chemistry, Bioorganic Medicinal Chemistry, Indian Journal of Pharmaceutical Science, Indian drug and
Bull. Korean Chem. Soc. etc
Library of SAC College of Pharmacy, B.G Nagara, Indian Institute of Science, Bangalore,
IITC, Hyderabad, IIT, Chennai.
The day to day development in this area will be updated by literature survey through Epublishing and current periodicals in library of SAC College of Pharmacy, B.G Nagara.
6
All the basic facilities required for synthetic pharmaceutical chemistry are available in
laboratories of SAC College of Pharmacy. For purification of the products TLC, Column
Chromatography, HPLC and other facilities such as UV, FTIR are also available in our
College.
7.2 METHOD OF COLLECTION OF DATA:
The chemical structure of the synthesized compounds shall be established on the basis of
physical, chemical and analytical data. Melting point of new compounds shall be
determined in open capillary tube. They are expressed in degree Celsius.
The compound synthesized will be characterized by UV, IR, H1 NMR, C13 NMR and Mass
spectral data. H1 NMR, C13 NMR and Mass spectra will be collected by sending the sample
to other advanced research centers like IISc Bangalore, IICT Hyderabad & IIT Chennai.
All the molecules will be screened for their pharmacological activity in our laboratory.
7.3
Does the study require any investigation or interventions to be
conducted on patients or other humans or animals?
YES
7.4
Has ethical clearance been obtained from your institution in case of 7.3?
WILL BE OBTAINED
7
ENCLOSURE: III
8. REFERENCES:
1. Rosaria G, Laura DL, Stefania F, Rita C, Giovambattista DS, Lara C et al.
Development of 3-substituted-1H-indole derivatives as NR2B/NMDA receptor
antagonists. Bioorg Med Chem 2009;17:1640-7.
2. Bastian T, Bastian F, Dirk S, Kai-Uwe S, Thomas W, Bernhard W.
Conformationally constrained NR2B Selective NMDA receptor antagonists derived
from ifenprodil: synthesis and biological evaluation of tetrahydro-3-benzazepine1,7-diols. Bioorg Med Chem 2010;18:8005-15.
3. Gaelle R, Beatrice L, Laurent B, Yann B, Christine C, Michelle O et al. Synthesis,
radiosynthesis and in vivo evaluation of 5-[3-(4-benzylpiperidin-1-yl)prop-1,3dihydrobenzoimidazol-2-[11C]one, as a potent NR1A/2B subtype selective NMDA
PET radiotracer. Bioorg Med Chem 2003;11:5401-8.
4. Ahmed E.H, Pascale M, Gerard L, Jean-Philippe R. Synthesis, activity and
modeling studies of 3-and 4-(sulfo-and sulfonamidoalkyl)pyridine and piperidine-2carboxylic acid derivatives as analogs of NMDA receptor antagonists. Bioorg Med
Chem 1995;3(9):1183-1201.
5. Takeshi F, Hiroshi Y, Mikako O, Le B, Morio N, Mamoru H et al. Synthesis and
biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents
for NR2B subtype of NMDA receptor. Bioorg Med Chem 2010;18:7497-7506.
6. Francesco B, Savina F, Nicola AC, Marcello L, Roberto P, Vincenzo T. A
multireceptorial binding reinvestigation on an extended class of ligands: N-[ω(indan-1-yl and tetralin-1-yl) alkyl] derivatives of 3,3-dimethylpiperidine reveal
high affinities towards σ1 and EBP sites. Bioorg Med Chem 2001;9:1325-35.
7. Ashutosh B, Dirk S, Bernhard W. Synthesis and NMDA receptor affinity of
fluorinated dioxadrol analogues. Bioorg Med Chem 2010;18:4095-4102.
8. Thomas P, Oliver S, Daniela N, Patrick R, Michael LB, Christian RN. New
polyamine-sensitive
inhibitors
of
the
NMDA
receptor:
synthesis
and
pharmacological evaluation. Eur J Med Chem 2007;42:175-97.
9. Erik A, Stefan P, Achim B, Lyn SP, Sajinder KL, Hans-Jurgen W et al. Towards
NR2B receptor selective imaging agents for PET-synthesis & evaluation of N-[11C](2-methoxy)benzyl(E)-styrene-,2-naphthyl- and 4-trifluoromethoxyphenyamidine.
Bioorg Med Chem 2006;14:6307-13.
8
10. Amir PT, Edward RW, Richard MW, Ravindra BU, John FWK. Structural-activity
relationship for a series of 2-substituted 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles:
potent subtype-selective inhibitors of N-methyl-D-aspartate (NMDA) receptors.
Bioorg Med Chem Lett 1999;9:1619-24.
11. Cara AM, Scott JM, Ernest EM, Rose S, Yesim AT, Natalie K et al. Synthesis,
structural activity-relationship, and biological evaluation of novel amide-based
allosteric binding site antagonists in NR1A/NR2B N-methyl-D-aspartate receptors.
Bioorg Med Chem 2009;17:6463-80.
12. Karine A, Adeline M, Laetitia M, Jacques N, Pierre P, Maurice G et al. Reactive
derivative for affinity labeling in the ifenprodil site of NMDA receptors. Bioorg
Med Chem Lett 2008;18:2765-70.
13. Xiaowu D, Yujie L, Jingying Y, Chaoyi J, Jing C, Tao L et al. Identification of
SVM-based classification model, synthesis and evaluation of prenylated flavonoids
as vasorelaxant agents. Bioorg Med Chem 2008;16:8151-60.
14. Sathish NK, Hemamalini K, Rajendra P. Vasodilator activity of 4-(4benzylidenepiperidin-1-yl)-1-(4-fluorophenyl) butan-1-ol. Adv Phamacol Toxicol
2008;9(1):123-5.
15. Joseph V, Pierre M, Nicole P, Pierre B, James PS, Pierre G et al. 1,2-Ethane bis-1amino-4-benzamidine is active against several brain insult and seizure challenges
through anti-NMDA mechanisms targeting the 3H-TCP binding site and antioxidant
action. Eur J Med Chem 2010;45:3101-10.
9
09 Signature of Candidate
(PATEL VIJAYKUMAR AMRUTLAL )
10 Remarks of the guide
11 Name and Designation
(In block letters)
11.1 GUIDE
Guide ship reference No. of RGUHS
ACA/CDC/PGT-MPH/SACP/36/200809
This work can be carried out in our
laboratory
Dr. B. RAMESH
M. Pharm.,Ph.D.,
Professor,
Department of Pharmaceutical
Chemistry,
S.A.C. College of Pharmacy,
B.G.Nagara.
Nagamangala(Taluk)
Mandya (Dist)-571448
Karnataka
11.2 Signature
11.3 Head of the Department
Dr. JAISHREE VAIJANATHAPPA
M. Pharm., Ph.D.,
Professor & Head, Department of
Pharmaceutical Chemistry.
S. A. C. College of Pharmacy,
B. G. Nagara.
Nagamangala(Taluk)
Mandya (Dist)-571448
Karnataka
11.4 Signature
12 12.1 Remarks of the Principal
12.2 Signature
10