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

1. Berstruktur sp, yi aktivitasnya tergantung pada struktur molekulnya. Contoh: -catecol amine (phenyl ethyl amine) -opiat gol penantren (morfin, codein, heroin) -penicillin -chloramphenicol, tetracyclin dan rifampicin Cirinya: -bekerja butuh reseptor -dosis kecil -sedikit saja terjadi perubahan struktur, sgt berpengaruh thd efek -efeknya nyata mempengaruhi sistem biologis Senyawa obat / bioaktif dikelompokan 2 gol, a.l: Senyawa bioaktif atau zat aktif obat dan reseptor I. PENDAHULUAN

2. Berstruktur non sp, yi aktivitas biologinya tidak tergantung pada struktur molekulnya. Contoh: -osmotic diuretics -antacids -chelating agent -laxant (lubricant) -emolient Cirinya: -bekerja tidk butuh reseptor -bekerja bersifat thermodinamika -dosis besar -perubahan dari struktur tidak mempengaruhi efek. Receptor are all specific molecules, molecule complexes or part of 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 conformation 3. Processing of signals resulting from drug-receptor interactions. 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 the drug, except that structure effects physico-chemical properties. Structural non specific drugs act by physico-chemical prossesess. Cirinya: -struktur tidak spesifik -perubahan struktur tdk mempengaruhi sec berarti thd efek -zat aktif bersifat thermodinamis -dosis besar

Ad.2. Impact of drug binding on receptor conformation The first Massenger + R + G-protein ---- MRG + effector ---- the second massenger will be released. 1. The simple action for produce an effect Examples: sympathomimetic and parasympathomimetic drugs -adrenergic -cholinergic 2. Preventing the receptor to bind with its endogenous ligand, without changing the conformation Examples: Curare 3. Changes in receptor conformation 3.1. Enhancing the affinity of the drug for the receptor inducet fit 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 Inhibiting inactivation

Transmembrane Ion Channels G PROTEIN and Second Messenger Impact of drug binding on receptor conformation

Receptor mediated activation of a G protein and the Resultant Effector interaction a)In the resting state, the  and  subunits of G protein are associated with one another, and GDP is boud to  subunit. b)Binding of an extracellular ligand (agonist) to a G protein-coupled receptor  exchange of GTP for GDP on the  subunit. c)The  subunit dissociates from the  subunit, which diffuses to interact with effector proteins. Interaction of the GTP-associated  subunit with an effector activates the effector. oIn some cases, the  subunit can also activate effector proteins. oDepending on the receptor subtype and the spesific G  isoform, G  can also inhibit the activity of an effector molecule. oThe  subunit posseses intrinsic GTPase activity, which leads to hydrolysis of GTP to GDP. This leads to reassociation of the  subunit with the  subunit and the cycle can begin again.

Ad. 3. Processing of signals resulting from drug-receptor interactions 1. Messenger : Catecholamines 2. Messenger : c. AMP Ex. L1 + R > G- protein > A C c. AMP L2 + 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: K1 R + O > RO > E < k2 Jml 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 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 -down regulation --- TCA (tricyclic acid) --- antidepressant Ex. Opiat toleransi 2. 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. Inactivastion Loss of ability a receptor to respond, to stimulation by a drug 5. Refractory After 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 selectivity Drug – receptor interactions Specificity: tissue, systems, organ where receptors are distributed (compartement) Ex. Adrenergic and cholinergic Selectivity : drug interacts preferentially on particular receptor types or sub types. Ex. Propanolol: non selective ---- antagonist of ß 1 and ß2 Atenolol : ß 1 –selective, ß2 less Terbutalin : agonist of ß2

Antaraksi obat dg reseptor, ada bbrp teori a,l: 1.Clark & Gaddum (Pendudukan reseptor ) 2.Ariens & Stephenson( O+R –> kompl --- efek) 3.Laju reaksi 4.Charniere 5.Kesesuaian yang terimbas 6.Penggangguan makromolekul III. Teori kerja Obat ditingkat molekul:

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 & enzymatic altering the process. Ligands is chemical must have affinity for the receptors. Drug-Recetor theories Hypothesis of Clark The pharmacological effect depends on the percentage of recetors occupied. The drug must have affinity for the receptor. If all receptors are occupied maximum effect is obtained. Lock and key hypothesis The drug molecule must” fit into a receptor” like a “key fits into a lock” (intrinsic activity). Conformation and chemistry of receptors and ligands O + R  OR komplex ---- efek farmakologi.

Drug shape 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. The 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 way that a key is complementary to a lock. Lock and key hypothesis The drug molecule must” fit into a receptor” like a “key fits into a lock” (intrinsic activity). Receptor Drug molecules with specifics strukture was talled ligands 1Drug molecules 2Receptor 3Affinity (drug bind to the resceptor, blocking of receptor) 4Intrinsic activity (drug bind to the receptor and result in pharmacological action) AFFINITY AFFINITY AND INTRINSIC ACTIVITY

2. Teori Ariens dan Stephenson Antaraksi obat dengan reseptor mencakup dua tahap, yaitu a.Pembentukan kompleks obat-reseptor b.Menunjukkan efek Persyaratannya, a.l : 1.Senyawa obat harus punya affinitas kuat thd reseptor 2.Aktivitas intrinsik 3.Struktur spesifik Hypothesis of Ariens and Stephenson (Occupation theory) In 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 Charniere Menerangkan mengapa suatu agonis, meskipun tdk dapat menggeser antagonis dari reseptornya, dapat bersaing dg antagonis sesuai dengan hukum aksi masa. Reseptor mempunyai 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 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 dg reseptor.

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 those in 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. Determinan molekuler dan seluler terhadap selektivitas obat

Stereoisomers  Have the same molecular formula and the same order of attachment of their atoms (the same connectivity), but different three-dimensional orientations of their atoms in space. –example: the cis-trans isomers of cycloalkanes

Drugs similar pharmacological action have usually some common structural 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 molekular Obat adl zat aktif yang sudah terbukti efektif, tidak semua zat aktif dapat digunakan sebagai obat. Fokus: Mekanisme kerja obat-obat terutama interaksi obat dg reseptor shg terjadi suatu efek. Gambar: perubahan konformasi suatu enzim yg diimbas oleh substratnya Obat dibagi dalam 2 kelompok besar, yaitu: 1.Struktur spesifik, utk bekerja membutuhkan reseptor --- perubahan pd sistemefektor, ada efek dan dapat diamati. 2.Struktur non spesifik, tidak butuh reseptor ---- tidak ada efek. mis: Antacida, laksan osmotik / garam (MgSO4), gliserin, Na3 PO4 Diuretik osmotik

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.