Sn, 23-11-09, BBC3-K17: 14.0 – 15.0 WIB DATTEN B DAN A. JAS

I. PENDAHULUAN

S b t / bi ktif dik l k 2 l l

Senyawa bioaktif atau zat aktif obat dan reseptor

1. Berstruktur sp, yi aktivitasnya tergantung pada struktur molekulnya. Contoh:

Senyawa obat / bioaktif dikelompokan 2 gol, a.l:

Contoh:-catecol amine (phenyl ethyl amine)-opiat gol penantren (morfin, codein, heroin)-penicillinp-chloramphenicol, tetracyclin dan rifampicin

Cirinya:-bekerja butuh reseptor-dosis kecil-sedikit saja terjadi perubahan struktur, sgt berpengaruh thd efek

f k t hi i t bi l i-efeknya nyata mempengaruhi sistem biologis

2. Berstruktur non sp, yi aktivitas biologinya tidak tergantung pada struktur molekulnya.

Contoh:-osmotic diuretics

t id-antacids-chelating agent-laxant (lubricant)emolient-emolient

Cirinya:-bekerja tidk butuh reseptorbekerja tidk butuh reseptor-bekerja bersifat thermodinamika-dosis besar-perubahan dari struktur tidak mempengaruhi efek.p p g

Receptor are all specific molecules, molecule complexes or part of these, which bind the drug chemically and this complex exertsof these, which bind the drug chemically and this complex exerts a pharmacological action.

II. Pharmacology molecular concept 1. Drugs that do not fit the drug-receptor model

2. Impact of drug binding on reseptor conformation2. Impact of drug binding on reseptor conformation

3. Processing of signals resulting from drug-receptor interactionsinteractions.

4. Celluler regulation of drug-receptor interactions

5. Moleculler and celluler determinants of drug selectivity

In order to have a good “fit” to only one type receptor ⇒ a drug molecule must be sufficiently unique in shape, charge, structure, etc, to prevent its binding to other receptors.

Ad.1. Drugs that do not fit the drug-receptor model

Ativity by not receptor as mediated mechanism. Structure non sp drugs are those in which the pharmacological action is not directly dependent on the chemical structure of theaction is not directly dependent on the chemical structure of the drug, except that structure effects physico-chemical properties.

Structural non specific drugs act by physico-chemical prossesess. Cirinya:y-struktur tidak spesifik-perubahan struktur tdk mempengaruhi sec berarti thd efek -zat aktif bersifat thermodinamis-zat aktif bersifat thermodinamis-dosis besar

Ad.2. Impact of drug binding on receptor conformation

Th fi t M + R + G t i MRG + ff t th dThe first Massenger + R + G-protein ---- MRG + effector ---- the second massenger will be released.

1 The simple action for produce an effect1. The simple action for produce an effectExamples: sympathomimetic and parasympathomimetic drugs-adrenergic-cholinergiccholinergic

2. Preventing the receptor to bind with its endogenous ligand, without changing the conformationExamples: CurareExamples: Curare

3. Changes in receptor conformation3.1. Enhancing the affinity of the drug for the receptor ------ inducet fitg y g p

receptor altering the action of the receptor.

Ex : insulin analog --- stimulate all the insulin receptor to the same extent despite slightly different amino acid sequence.

3.2. Inhibiting ------ inactivation

Transmembrane Ion ChannelsImpact of drug binding on receptor conformation

Transmembrane Ion ChannelsG PROTEIN and Second Messenger

Receptor mediated activation of a G protein and the Resultant Effector interactionthe Resultant Effector interaction

a) In the resting state, the α and βγ subunits of G protein are associated with one another, and GDP is boud to α subunit.

b) Binding of an extracellular ligand (agonist) to a G protein-coupled receptor ⇒) g g ( g ) p p pexchange of GTP for GDP on the α subunit.

c) The βγ subunit dissociates from the α subunit, which diffuses to interact with effector proteins. Interaction of the GTP-associated α subunit with an effector activates the effector.

o In some cases the βγ subunit can also activate effector proteinso In some cases , the βγ subunit can also activate effector proteins.o Depending on the receptor subtype and the spesific Gα isoform, Gα can also inhibit the activity of an

effector molecule. o The α subunit posseses intrinsic GTPase activity, which leads to hydrolysis of GTP to GDP. This leads to

reassociation of the α subunit with the βγ subunit and the cycle can begin again.

Ad. 3. Processing of signals resulting from drug-receptor interactions

1. Messenger : Catecholaminesg

2. Messenger : c. AMPEx. L1 + R -------> G- protein ---------------> A C5 ------ c. AMP

L2 + R > G protein > A Ci >!! c AMPL2 + R -------> G- protein ---------------> A Ci ----->!! c AMP

1. Clark dan Gaddum:Intensitas efek berbanding langsung dg jml reseptor yg ditempati oleh senyawa obat. Antaraksi obat-reseptor sesuai dg hukum aksi masa seperti persamaan ini:

K1R + O ----------------> RO ----------> E

<--------------k2

Jml reseptor yg ditempati obat tgt pada konsentrasi obat pada konpartemenJml reseptor yg ditempati obat tgt pada konsentrasi obat pada konpartemen reseptor dan juml keseluruhan reseptor, efek obat lebih kuat bila jml reseptor yg ditempati semakin banyak. Teori ini tidak dapat menjelaskan ada obat tertentu bekerja sbg agonis danTeori ini tidak dapat menjelaskan ada obat tertentu bekerja sbg agonis dan obat lain dg struktur yg sama bekerja sbg antagonis.

Ad. 4. Celluler regulation of drug-receptor interactions

Drug ---- Foreign body to our cells, prinsiple homeostatis

1. No of receptors-upregulation -- beta-blocker-upregulation -- beta-blocker-down regulation --- TCA (tricyclic acid) --- antidepressantEx. Opiat ------ toleransi

2 T h h l i t l i t t j di2. Tachyphylaxis --- toleransi cepat terjadi-reduce effect produced after repeated administration

3. Desensitization (Ketidak pekaan)-homologous ----- decrease response of a single class of receptor-heterologous ---- multiple class

4 Inactivastion4. InactivastionLoss of ability a receptor to respond, to stimulation by a drug

5. RefractoryAft t i ti l t d i d f ti i i d b f th tAfter a receptor is stimulated, a priod of time is required before the next drug-receptor interaction can produce an effect.

Ad.5. Moleculler and celluler determinants of drug selectivityDrug – receptor interactionsDrug receptor interactions

Specificity: tissue, systems, organ where receptors are distributed (compartement)E Ad i d h li iEx. Adrenergic and cholinergicSelectivity : drug interacts preferentially on particular receptor types or sub types.Ex Propanolol: non selective ---- antagonist of ß 1 and ß2Ex. Propanolol: non selective ---- antagonist of ß 1 and ß2

Atenolol : ß 1 –selective, ß2 lessTerbutalin : agonist of ß2

A t k i b t d t d bb t i lIII. Teori kerja Obat ditingkat molekul:

Antaraksi obat dg reseptor, ada bbrp teori a,l:

1. Clark & Gaddum (Pendudukan reseptor )( p )

2. Ariens & Stephenson( O+R –> kompl --- efek)

3. Laju reaksi

4 Ch i4. Charniere

5. Kesesuaian yang terimbasy g

6. Penggangguan makromolekul

Receptor is specifics molecule or complex molecule wich bind of drug

Conformation and chemistry of receptors and ligands

Receptor is specifics molecule or complex molecule wich bind of drug as chemically and this complex exerts a pharmacological action -----> pharmacolgical activity, in this case biological altering system. Sach as: membran cell altering the permeability --- ion-ion diffusion & enzymaticmembran cell altering the permeability ion ion diffusion & enzymatic altering the process.

O + R OR komplex ---- efek farmakologi.

Ligands is chemical must have affinity for the receptors.

Drug-Recetor theories

Hypothesis of ClarkThe pharmacological effect depends on the percentage of recetors occupied. The drug must have affinity for the receptor. If all receptors are occupiedThe drug must have affinity for the receptor. If all receptors are occupied maximum effect is obtained.

Lock and key hypothesisThe drug molecule must” fit into a receptor” like a “key fits into a lock”The drug molecule must” fit into a receptor” like a key fits into a lock” (intrinsic activity).

Drug shapeThe shape of a drug molecule must be such as to permit binding to its receptor site. Optimally the drug’s shape is complementary to that of the receptor site in the same

In order to have a good “fit” to only one type receptor ⇒ a drug molecule must be sufficiently unique in shape charge structure etc to prevent its binding to other receptors

Optimally, the drug s shape is complementary to that of the receptor site in the same way that a key is complementary to a lock.

unique in shape, charge, structure, etc, to prevent its binding to other receptors.

Lock and key hypothesisThe drug molecule must” fit into a receptor” like a “key fits into a lock” (intrinsic activity).

ReceptorDrug molecules with specifics strukture was talled ligands

1 Drug molecules2 Receptor

AFFINITY

3 Affinity (drug bind to the resceptor, blocking of receptor)

4 Intrinsic activity (drug bind to the receptor and res lt inreceptor and result in pharmacological action)

AFFINITY AND INTRINSIC ACTIVITY

2. Teori Ariens dan StephensonAntaraksi obat dengan reseptor mencakup dua tahap, yaitu ta a s obat de ga esepto e ca up dua ta ap, ya tua. Pembentukan kompleks obat-reseptorb. Menunjukkan efek

Persyaratannya, a.l :1. Senyawa obat harus punya affinitas kuat thd reseptor2. Aktivitas intrinsik3 St kt ifik3. Struktur spesifik

Hypothesis of Ariens and Stephenson (Occupation theory)In addition to affinity anather constant “intrinsic activity” or “efficacy” must beIn addition to affinity, anather constant, intrinsic activity or efficacy must be present. Still, the ineffective substance may block or inhibit the receptor. Effectiveness last as long as the receptor is occupied.

3. Teori CharniereMenerangkan mengapa suatu agonis meskipun tdk dapat menggeserMenerangkan mengapa suatu agonis, meskipun tdk dapat menggeserantagonis dari reseptornya, dapat bersaing dg antagonis sesuai denganhukum aksi masa. Reseptor mempunyaidua kedudukan a. l:dua kedudukan a. l: 1. Kedudukan kritis atau yang khas, yaitu berinteraksi dg ggs kromofor

senyawa agonis.2. Kedudukan non kritis atau tidak khas, yaitu membentuk kompleks dg

ggs nonpolar senyawa antagonis.

Menurut Chaniere baik agonis maupun antagonis terikat pada kedudukanMenurut Chaniere, baik agonis maupun antagonis terikat pada kedudukan yg khas dg ikatan lemah secara reversibel. Dsp itu antagonis juga terikat secara tidak khas melalui ikatan hidrofob dan Van der Waals serta transfer muatan Persaingan agonis dg antagonis terjadi pada kedudukan yg khas dgmuatan. Persaingan agonis dg antagonis terjadi pada kedudukan yg khas dg reseptor.

Determinant (faktor penentu):

Determinan molekuler dan seluler terhadap selektivitas obat

Determinant (faktor penentu):The chemical structure may be very much different, yet the pharmacological action are similar. A slight modification in chemical structure does not produce a dramatic chang in pharmacological action. Structural specific drugs are thosea dramatic chang in pharmacological action. Structural specific drugs are thosein which the pharmacological action dependent directly on the chemical structure of the drug, wichh attaches itself to a three-dimensional structure of a reseptor in the biophase. Prerequisites of the binding of a drug to receptor are: chemical, reactivity,presence of fungsional groups, electonic distribution and topographic mirror-like image of the receptor.

StereoisomersStereoisomersHave the same molecular formula and the same order f tt h t f th i t (th ti it )of attachment of their atoms (the same connectivity),

but different three-dimensional orientations of their atoms in space.p– example: the cis-trans isomers of cycloalkanes

d

CH3 HCH3CH3

cis 1 4 Dimethyl

andH CH3HH

trans 1 4 Dimethylcis-1,4-Dimethyl- cyclohexane

trans-1,4-Dimethyl- cyclohexane

Drugs similar pharmacological action have usually some common structural caracteristics with functional groups in similar spatialstructural caracteristics with functional groups in similar spatial direction. A slight modification in chemical structure may produce dramatic change in pharmacological action (from incresed activity to antagonism.

Konsep Farmakologi molekularObat adl zat aktif yang sudah terbukti efektif, tidak semua zat aktif dapat Obat ad at a t ya g suda te bu t e e t , t da se ua at a t dapatdigunakan sebagai obat.

Fokus: Mekanisme kerja obat-obat terutama interaksi obat dg reseptor shg terjadi suatu efekterjadi suatu efek.Obat dibagi dalam 2 kelompok besar, yaitu:1. Struktur spesifik, utk bekerja membutuhkan reseptor --- perubahan pd sistemefektor,

ada efek dan dapat diamatiada efek dan dapat diamati.2. Struktur non spesifik, tidak butuh reseptor ---- tidak ada efek.

mis: Antacida, laksan osmotik / garam (MgSO4), gliserin, Na3 PO4Diuretik osmotik

Gambar: perubahan konformasi suatu enzim yg diimbas oleh substratnya

Pada gambar ini terjadi gaya antaraksi antara rantai protein, molekul substrat dan ion-ion yang ada dalam larutan diberi tanda H untuk gaya hidrofob + dan – untuk gaya elektrostatik. Kompleks protein-substrat yang terbentuk dapat berdissosiasi dan protein terlipat kembali ke konformasi semula.