agonis-antagonis
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PED0MAN KULIAH( HANDOUT)
AGONIS DAN ANTAGONIS
OLEHDRS H ISMA’IL Msi
Apt2012
FASE FASE KERJA OBAT :
FASE FARMASETIK HANCUR DANLARUT
BIO PHARMSI : KIMIA FISIS SEDIAN OBAT DAN BENTUK SEDIAN OBAT.
CARA PEMBERIAN : PO, PARENTAL, INHALASI ,TOPIKAL, VAGINAL DAN REKTAL.
BENTUK SEDIAAN : TABLET, CAPSUL, SUPOS, SUSPENSI , SIRUP, INJEKSI
FASE PARMASETIK
ABSORBSI , DISTRIBUSI METABOLISME EKRESI. - SEL. - QSAR : - KELARUTAN DALAM LEMAK ( LOG P) HANSCH FUYITA,HANSCH LEO, REKKER , REKKER DIPERBAIKI DAN CHEMDRAW ULTRA 8.0.TEMPAT ABS. + ; BIO TRANSF. + ; INTERKS. RESEP. + - STRIK PARAMETER , ISOSTERIK BIOSTERIK ( STERIO ISOMER GEOMETRIS ( R, S, E DAN Z) OPTIK ISOMER ( - DAN + ) KONFORMASI ISOMER.TEMPAT ABS. - ; BIO TRANSF. +/- ; INTERKS. RESEP. + - ELEKTRONIK PARAMETER ( INDUKSI, RESONANSI, RHO, SIGMA , SIGMS STAR, PI kA.TEMPAT ABS. +/- ; BIO TRANSF. + ; INTERKS. RESEP. +
C
Cl
H
C(Z)
Br
H
C
Cl
H
C(E)
H
Br
TRANS CIS
C (R)
COOH
CH3HO
HC (S)
COOH
OHH3CH
LEVODEXTRO
d l
NOMOR PRIORITAS; I>Br>Cl>SO2R>SOR>SR>SH>F>OCOR>OR>OR>OH>NO2>NO>NHCOR>NR2>NHR>NH2>C(X)3 X= HALOGEN>COX>
CO2R> COOH>CONH2> COR>CHO>CR2OH>CH(OH)R>CH2OH> > > CR=CR2>C6H5>CR3>CHR2>CH2R>
CH3>D>H>LONE PAIR ELECTRON.C CR
_C CH
E = ENTGEGEN= BERLAWANAN.Z=ZUSAMMEN= BERASAMA-SAMA
NH2 SULFONASI
ß-NAFTIL AMINKARSINOGENIK
NH2
SO3H
HO3S
2-NAFTILAMIN-6-8-SULFONIK ASIDTIDAK KARSINOGEN
asam folat (METABOLIT)
methotrexate ( ANTI METABOLIT)
HN
OHN O
(Z)uracil ( METABOLIT )
HN
OHN O
(E) F
FLUOR URACIL ( ANTI METABOLIT)
C(S)
CH2
H
NH
CHCH3H3C
C(S)
CH2
H
NH
CHCH3H3C
HO
OH NHSO2CH3
OCH2OH OH
C(R)
H OH
CH2
NH
CHH3C CH3
OCH2
C(R)
H OH
CH2
NH
CHH3C CH3
NHCOCH3
ISOPRENALIN SOTALOL OBAT β-ADRENERGIK PROPANOLOL PRAKTOLOL
OBAT PEMBLOK β-ADRENRGIK
EFEK ELEKTRONIK DAN AKTIVITAS ZATPENGALKILASI. DAN MEKANISME DI
BAWAH:
N(CH2CH2Cl)2
N(CH2CH2Cl)2
N(CH2CH2Cl)2
N(CH2CH2Cl)2
H2N
Cl<
O2N
O2N<
<
SENYAWA HIDROLISIS AKTV. BIOLOGIS
100 +
20 +
9 -
1 -
NR
CH2CH2Cl
+
NR
CH2CH2Cl
CH2CH2ClNR
CH2CH2Cl
CH2CH2+
ION IMONIUM ION KRBONIUM
N
N N
N
O
OPO3-
CH2NH2-O3PON
N N
N
O
O
OPO3-
CH2NH2-O3PO
CH2CH2NH
CH2CH2Cl
N
N N
N
O
OPO3-
CH2NH2-O3PO
CH2CH2N
CH2CH2 N
N
N
N
O
-O3PO
-O3PO
O
NH2
R
S 1N
NITROGEN MUSTAR
O
P
NH
O
N
CH2CH2
CH2CH2
Cl
ClO
P
NH
O
N
CH2CH2
CH2CH2
Cl
Cl
SIKLOFOSMIT(PRA OBAT)
METAB. DI HATI
HO
4-HIDROKSISIKKLOFOSFAMID
O
P
H2N
O
NCH2CH2
CH2CH2
Cl
ClC
H
H
H2C
CHO
HO
P
H2N
O
N
CH2CH2
CH2CH2
Cl
Cl
CH
H
HCCHO
H
AKROLEIN
FOSFORAMID MUSTAR
+H -H+ +
O
P
H2N
O
N
CH2CH2
CH2CH2
Cl
Cl_
Cl_
O
P
H2N
O
N
CH2CH2
CH2
Cl
_
CH2
BENTUK AKTIF SIKLOFOSFMID
PO
N
H2C
H2C N
H
H
N
H2C
H2C N
H
CH3
N
H2C
H2C N
H
C2H5
N
H2C
H2C N
H
HC
N
H2C
H2C N
H
C3H7N
H2C
H2C N
H
C4H9
Log P = 0.27 LoG P = 0.79
LOg P =1.13Log P =1.45
CH3
CH3
Log P=1.62 Log P=2.03
AGONIS
AGONIS
AGONIS
ANTAGONIS
ANTAGOIS ANTAGONIS
N
H2C
H2C N
H
C6H12 N
H2C
H2C N
H
C8H17
N
H2C
H2C N
H
C9H19 N
H2C
H2C N
CH3
C3H6
Log P = 2.87 Lop P =3.7
Log P= 4.12Log P =3.6
ANTAGONIS ANTAGONIS
ANTAGONIS
ANTAGONIS
NH2C
H2C N
CH3
C2H4 O HC
Cl
N
H2C
H2C N
CH3
C2H4 N
H2C
Log P = 5.02
Log P = 4.98
ANTAGONIS
ANTAGONIS
I. ANTAGONIS H1N
C
H
X
CH2CH2N(CH3)2
X H FENIRAMIN Log p =3,21. X= Cl KLORFENIRAMIN Log P =3,77X = Br BRO FENIRAMIN Log P = 4,04
1.
N
O
DIPHENHIDRAMIN Log p = 3,53
2.
N
C
H
Cl
OCH2CH2
N
CH3
KLORFENOKSAMIN Log P = 3,63
3.
C
CH3
Cl
OCH2CH2N(CH3)2
KARBINOKSAMIN Log P = 3,41
4.N
N
H2C
CH2
H
N
N
5.
ANTAZOLIN Log P = 3,95
II. ANTAGONIS H21/SIMITIDIN
NNH
H3C CH2
S
H2C
CH2
HN
C
HN
NCN
CH3
Log P: 0,79 pKa = 6,8 ( HB )+
2. Ranitidin
NO
O
HC
C
HN
NHCH3
CH2
H2C
S
H2C
O
H2C
pKa = 2,72 : 8,2 ( HB )
N
H3C
H3C
Log P: 1.2
3. FAMOTIDIN
N
S
CH2
NCH2N
H2N
SCH2
H2C
NH
CNSO2NH2
NH2
Log P: 0.06
4 Roksantidin
NCH2
O
H2C
CH2
H2C
NH
CCH2
O
O
C
O
CH3
Log P: 1,255. NIZATIDIN
NO
O
HC
C
NHCH3NH
H2C
CH2
S
S
H2C
NH3C
H3C
Log P: 2,63
III. ANTAGONIS H3
HN
N
N C
S
NH
THIOPERAMID Log P = 2,16
HN
N
H2C
CH2
H2C
S NH
NH H2C
Cl
CLOBENPROPIT Log P = 3,4
HN
N
H2C
CH2
H2C
CH2
HN
CH2
H2C
CH
H1/H3 DUEL ANTAGONIS 4,25
N
H2C
CH2
H2C
O
H2C
N
JNJ 5207852 Log P =3,42
O
CH2
H2C
NH3C
CN
ABT-239 Log P = 4,09
1
2 3
34
NH2
H2C
CH2
HN
N
4-METHYLHISTAMIN Log p = O,76MEMPUNYAI AFFINITAS LEBIH KUAT100 X UNTUK H4 RESEPTOR DENGAN
GERBAGAI MACAM TYPE RESPTOR YNG LAIN.
CH3
HN
Cl
C
O
N N CH3
JNJ 7777120 Log P =1,32ANTAGONIS H4
1 2
Histamin log P = -1,09
H4 untuk rhiniitis
O
CH3
CH2OH
CC
H
O O
ALDOSTERON Log p 1,22
O
O
O
SCOCH3
Log P: 2,9SPIRIRONOLAKTON
2.
O
O
O
KANRENON LOG P =2,95
C
H2CC
O
C
H2C
O
O-
SCoA
CH3
HO C
H2CCH
OH
C
H2C
O
O-
SCoA
CH3
HO
3-HIDROK SI-3-METILGLUTANIL-K oA(HMG-K OA)
HMG-K oAREDUK TASE
NADPH + H+
NADPH + H+
BENTUK ANTARAMEVALONAT
C
H2CCH2
OH
C
H2C
O
O-
CH3
HO
CH
H2CCH
OH
C
H2C
O
O-
CH2
HO
H2COC
O
CH
CH3
H3C
CH
H2CCH
O
C
H2C
O
CH2
HO
H2COC
O
CH
CH3
H3C
LOVASTATIN BENTUK AK TIVLOVASTATIN
H3C H3C
CH
H2CCH
O
C
H2C
O
CH2
HO
H2COC
O
C
CH3
H3C
H3C
CH
H2CCH
O
C
H2C
O
CH2
HO
H2COC
O
CH
CH3
H3CCH3
Log P = 2,61MEVASTATIN10 Mg 1 DD
Log P 3,64SIMVASTATIN ( ZAK OR ,
SIMBIDO)5- 10 Mg 1 DD
CH
H2CCH
O
C
H2C
O
CH2
HO
H2COC
O
C
CH3
H3C
H3C
CH
H2CCH
O
C
H2C
O
CH2
HO
H2COC
O
CH
CH3
H3CCH3
Log P = 2,61MEVASTATIN10 Mg 1 DD
Log P 3,64SIMVASTATIN ( ZAK OR ,
SIMBIDO)5- 10 Mg 1 DD
CH
H2CCH
OH
C
H2C
O
CH
HO
HC
CH
H2CCH
OH
C
H2C
O
CH2
HO
H2COC
O
CH
CH3
H3C
HO
OH
LOG P= 0,94 10 mg 1 DD
PRAVASTATIN (PRAVACOL, MEVALOTIN)
OH
F
LOg P = 3,5FLUVASTATIN
( LESCOL)40 MG 1 DD
Na+
CH
H2CCH
OH
C
H2C
O
CH
HO
HC
OH
N N
CH
NH3C SO2CH3
CH3
CH3
F
2
Ca++
ROSUVASTATIN ( CRESOR)Log p = O,59 K ENY TAAN 0,13 ( HIDROPHILIC)
Cl
HC(S)
C
N
S
OOCH3
(+)-(S)-a-(2-CLOROFENIL)-6,7-DIHIDROTHIENO [3,2-C}PY RIDINE- 5(4H)- ACETATE SULFATE.
CLOPIDOGREL
Cl
HC(S)
C
N
S
OO
Mg++
H3C
TERJ ADI 5 DAN 6 CICIN SAMA DENGAN ATP DAN ADPBERRTI BELUM ANTAGONIS
N
NN
N
NH2
O
OHOH
HHHH
OPO
O-
O
PO
O
P
O-O
O- O-
N
NN
N
NH2
O
OHOH
HH
HH
OPO
O-
O
P-O
O
O-
N
NN
N
NH2
O
OHOH
HH
HH
OP-O
O-
O
N
NN
N
NH2
O
OHOH
HHHH
OPO
O-
O
PO
O
P
O-O
O- O-
Mg+
N
NN
N
NH2
O
OHOH
HH
HH
OPO
O-
O
P-O
O
O-
Mg+
N
NN
N
NH2
O
OH
HH
HH
O
P-O
O
OADENILATSIKLSAE
ATP ATP K OMPLEK MAGNESIUM
ADPADP K OMPLEK MAGNESIUM
AGREGASI PLATELET
AMPSIK LIK AMP
BRONK O DILATATOR
Cl
HC(S)
C
N
S
OOCH3
(+)-(S)-a-(2-CLOROFENIL)-6,7-DIHIDROTHIENO [3,2-C}PY RIDINE- 5(4H)- ACETATE SULFATE.
CLOPIDOGREL
Cl
HC(S)
C
N
S
OO
Mg++
H3C
TERJ ADI 5 DAN 6 CICIN SAMA DENGAN ATP DAN ADPBERRTI BELUM ANTAGONIS
CLOPINDOGREL
Cl
C
N
COOCH3
H
S
H
ENZY M CY TOCROM P450
-
+
H
Cl
C
N
COOCH3
H
S
H
-
+
H
-On O
Cl
C
N
COOCH3
H
S
H
-
+
H
O-
Cl
C
N
COOCH3
H
S
H
OH
CLOPIDOGREL ( PRO-DRUG)
KALAU DIMETABOLISME ?
KENAPA TIDAK DICINCIN BENZEN DAN IKATAN RANGKAP SATUNYA?
JADI ANTAGONIS RESEPTOR ADP
• lanjut
Cl
C
N
COOCH3
H
S
H
O
H
O
H
H
Cl
C
N
COOCH3
H
S
H
O
H
OH
H
METABOLIT AK TIF CLOPIDOGREL
Cl
C
N
COOCH3
H
S
H
O
H
OH
S
Mg++
Mg++
K OMPLEK Mg CLOPIDOGREL7 CINCIN
CYSTEIN
Y2P12
C(S)
HC
N
Cl
OH3CO
S
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
C+
O
O
O
OHO
O
Mn
O
OH
OK SIDASI DENGAN K MnO4 DALAM H2SO4
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
C+
O
O
Mn
OH
OH
MnO
O
O
OK HCl+ MnO
O
O
OH + KCl
H+
H+
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
C+
O
O
Mn
O+
O+
H
H
H
H
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
C+
O
O
Mn++
-2H2O
HO
H
HOH
C(S)
HC
N
Cl
OH3CO
(Z)
S
O
O
H
H
HO
HO
TAK STABIL
-Mn++
C(S)
HC
N
Cl
OH3CO
(Z)
SH
O
O
H
HO
OH
C(S)
HC
N
Cl
OH3CO
(Z)
SH
O
O
OH
-H2O
(S )-2-(1-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-mercapto-1,2,5,6-tetrahydropyridin-3-yl)-2-oxoacetic acid
DENGAN ADANY A CLOPINDOGREL AK AN MENURUNK AN INTENSITAS WARNA K MnO4
H+
C(S)
HC
N
Cl
OH3CO
S
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
C+
O
O
O
OKO
O
Mn
O
OK
O
H
H
C(S)
HC
N
Cl
OH3CO
(Z)
S
C+
O-
O
H
K+MnO2
C(S)
HC
N
Cl
OH3CO
(Z)
S
O
O
H
H
HOH
HO
HO
HO
TAK STABIL
C(S)
HC
N
Cl
OH3CO
(Z)
SH
O
O
H
HO
OH
C(S)
HC
N
Cl
OH3CO
(Z)
SH
O
O
OH
OK SIDASI DENGAN K MnO4 SUASANA BASA
(S )-2-(1-(1-(2-chlorophenyl)-2-methoxy-2-oxoethyl)-4-mercapto-1,2,5,6-tetrahydropyridin-3-yl)-2-oxoacetic acid
-OH ( KOH)
DENGAN ADANYA CHLOPINDOGREL AKAN MENURUNKAN INTENSITAS WARNA KMnO4
ANTAGONIS DOPAMINDOPAMIN ADALAH SENYAWA YANG BERASAL
DARI SENYAWA L-DOPA YANG KEHILANGAN CO2.
DOPAMIN DALAM DOSIS RENDAH DAPAT MERANGSANG RESEPTOR DOPAMIN, DOSIS LEBIH
BESAR BETA-RESEPTOR DAN DASIS TINGGIMERANGSANG ALPHA- RESEPTOR’
DOPAMIN DIGUNAKAN VASOPRESORTERUTAMA UNTUKPENGOBAT SYOK, PAYAH
JANTUNG AKUT ATAU KRONIK.
DOPAMIN TAK AKTIF BILA DIGUNAKAN PO,JADI DIGUNAKAN SECARA IV ( INFUS),
T1/2 ELIMINASI 1-2 MNT. DOSIS ;5μg/ KG BB/ MNT ATAU 0,175- 0,250mg/ MNT.
metklorpropamid (memperkuat motilitasdan pengosongan lanbung, perstaltik dan
anti emetis) 2,04domperidon ( anti emetis, anti peristaltik
tukak lambung) 1,8
tetrahidropalmetin (analgetika) 3,14 chlopromazin (antipsikotik, antihistaninanntikholerergik, anti dopamin)
HOHO
CH2
H2CNH2
DOPAMIN 0,58
Cl
H2N
CCH2
O
H2C
CH2
N
CH3
CH3
CH3
OHN
N
NCH2
H2C
CH2
N NH
Cl
O
O
N
O
OO
OH
CH3
CH3
CH3
H3CN
S
CH2CH2CH2NCH3
CH3
HOHO
CH2
HC
(S)NH2
HOOC
L= DOPA
- CO2
penf luridol ( anti psikotik) 7,43f lufenthixol (antipsikotik) 8,18
clomipramin ( trisiklik antidepresan) 4,8
N
CH2CH2CH2
Cl
N
CH3
CH3
HCl
F
CH
H2C
CH2
H2C
N
OH
Cl
CF3
F
CLOZAPINE 3,71
NH
N
Cl
N
NCH3
S
F3C
N
N
OC
H2C
O
CH2H2C
CH2H2C
CH2H2C
CH2H3C
azaperzon (neuroleptik sedativ) 3,1benperidol ( neuroleptik) 3,44
butaclamol ( antipsikotik) 4,29perazin ( antipsikotik ) 3,44
N N
N
H2C
CH2
H2C
C
O
F
HN
NHC
CH2
CH2
N
H2CH2C
H2C
CH2
H2C O
F
N
H
OH
H
CF
FFHCl N
S
H2CCH2
H2CN
NCH3
lozapine ( schizophrenia)f luphenazin (antipsikosomatik)
haloperidol ( antipsikotik) 3,49 ziprasidon ( antipsikotik) 4,67
F
C
H2C
CH2
H2C
NO
OH
Cl
N NN S
Cl
HN
O
N
S
H2CCH2
H2C
N
NCF3
O
N
Cl
N
NCH3
NH2
H2C
CH2
HN
N
CH3
4-METYL HISTAMIN-0,76H4 ANTAGONIS
NH2
H2C
CH2
HN
N
HISTAMIN -1,09
NH2
CHCH2
HN
N
- METHYL HISTAMIN-0,77H3 ANTAGONIIS
H3C
NH2
H2C
CH2
HN
N
C2H5 NH2
H2C
CH2
HN
N
C3H7
NH2
H2C
CH2
HN
N
Cl
NH2
H2C
CH2
HN
N
BrNH2
H2C
CH2
HN
N
OH
NH2
H2C
CH2
HN
N
CN
NH2
H2C
CH2
HN
N
NH2
NH2
H2C
CH2
HN
N
NO2
4-ETHYL HISTAMIN-0,27 4-ETHYL HISTAMIN0,15 4-CHLOR HISTAMIN-0,72
NH2
H2C
CH2
HN
N
CNH2
H2C
CH2
HN
N
C
O
H OH
4-BROM HISTAMIN-0,38 4-HIDROKSI HISTAMIN-1,29 4-AMINO HISTAMIN-1,71
4-ALDEHI HISTAMIN-1,29 4-CARBOKSIL HISTAMIN -1,48 4-CYANO HISTAMIN-1
4-NITRO HISTAMIN-0,63
O
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