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prof. aza1 Analgetika kuat. Morfin dan turunannya, Referensi: Schunack, Mayer, Haake, Arzneistoffe. prof. aza.

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Presentasi berjudul: "prof. aza1 Analgetika kuat. Morfin dan turunannya, Referensi: Schunack, Mayer, Haake, Arzneistoffe. prof. aza."— Transcript presentasi:

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2 prof. aza1 Analgetika kuat. Morfin dan turunannya, Referensi: Schunack, Mayer, Haake, Arzneistoffe. prof. aza

3 2 Perkembangan  Apoteker Serturner, 1986, berhasil mengisolasi morfin dari opium, getah kering Papaver somniferum.  Awal isolasi senyawa fisiologis aktif yang bersifat basa dari tumbuhan, awal dari kimia alkaloid.  Morfin : analgetik, antitusif, ketergantungan psichis (kejiwaan) dan fisik.

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8 7 Papaver somniverum L (Papaveraceae)

9 prof. aza8 Endoethenotetrahydothebaine, semi sintetis dari tebain, alkaloid minor dari morfin. Dengan adisi dien, ternyata tebain berubah menjadi anagetik kuat.

10 prof. aza9 Penggambaran Robinson menonjolkan kerangka fenantren (cincin A, B dan C), penggambaran Awe menonjolkan derivat oktahidro-1-benzil-isokinolin. Cincin C dan D berhubungan secara trans, piperidin bentuk kursi, sikloheksen bentuk biduk. Konfigurasi 5R, 6S, 9R, 13S, 14R

11 prof. aza10 Efek farmakologi morfin  Analgetika kuat, dosis 10 mg sc  Penekanan pusat batuk pada dosis kecil  Depresi pernafasan, juga pada dosis terapi, dosis tinggi kelumpuhan pernafasan.  Sedatif, pada beberapa pasien euforia, menimbulkan ketergantungan, tolerensi dan peningkatan dosis.  stimulasi parasimpatik sentral, miosis.  Pada mencit ekor membentuk-S  Peningkatan tonus otot polos di perifer, sebaliknya opium karena kandungan papaverin meredakan tonus lambung.

12 prof. aza11 Sifat kimia  Morfin adalah alkaloid yang mempunyai amin tersier, bersifat basa dengan pKa≈8,1, dengan berbagai asam membentuk garam berupa kristal.  Morfin dengan adanya gugus hidroksi fenolik juga bersifat asam pKa ≈9,9 dapat bereaksi dengan logam alkali, tidak bereaksi dengan amoniak dalam suasana air.

13 prof. aza12 Larutan air morfin HCl dapat mengalami penguraian, akan dipercepat oleh adanya O 2, cahaya UV dan alkali. Dapat mengalami kopel oksidatif membentuk 2,2’- dehidrodimorfin (Pseudomorfin). Stabilitas akan dapat ditingkatkan dengan mengatur pH rendah dan penambahan atioksidant.

14 prof. aza13 Morfin bila dipanaskan dengan HCl atau H 2 SO 4 akan mengalami Penataulangan Apomorphin, diawali dengan protonasi hidroksi alkohol, pemutusan air. Dengan pemutusan jembatan eter dan cincin piperidin, maka cincin C mengalami aromatisasi. Pada pembentukan cincin baru dengan kehilangan satu proton maka akan terbentuk apomorfin.

15 prof. aza14 SAR morfin  Bila gugus hidroksi fenolik morfin diubah menjadi fenol eter, maka akan terbentuk senyawa tipe codein, dengan khasiat antitusif.  Perubahanan hidroksi fenolik umumnya mengurangi potensi analgetik, kecuali pada diamorfin/heroin.  Bila hidroksi alkoholik dieter, diester, dirubah jadi keton, maka akan meningkatkan potensi analgetik.  Aktivitas derifat dihidromorfin lebih sukar digeneralisasi.

16 prof. aza15 Reseptor Opiat  Beckett dan Casy, 1954 : Endorfin adalah ligand alami dari reseptor opiat.  Hughes dan Kosterliz: endorfin (  - lipotropin) adalah peptida yang terdiri dari 91 asam amino, yang mempunyai urutan asam amino yang sama, yakni Tyr(61)- Gly-Gly-Phe-Met (65).  Struktur mirip corticotropin, hormon adenohipofisa.

17 prof. aza16 Struktur primer  -Lipotropin dan Endorphin  -endorfin pada penggunaan intracerebral, 100x lebih kuat dibanding morfin. Endorfin mudah diurai enzim, sintesis analog yang stabil belum berhasil.

18 prof. aza17 Sintesis Ethylmorphin Sintesis Thebacon

19 prof. aza18 Sintesis Oxycodon

20 prof. aza19 Reaksi warna derivat morfin dan dihidromorfin  Reaksi Fröhde : Dengan Amoniummolibdat/H 2 SO 4 c, warna violet  Reaksi Mandelin: Dengan amonium vanadat/H 2 SO 4 c, warna violet. Pada kedua reaksi, dengan adanya H 2 SO 4 c akan terbentuk apomorfin, yang selanjutnya teroksidasi menjadi fenantrenchinon.

21 prof. aza20 Reaksi Marquis berlangsung tanpa melalui apomorfin. Dengan pereaksi formal dehid/H 2 SO 4, dari 2 morfin (sebagai fenol) akan membentuk produk kondensasi dimer. Warna violet, karena terbentuk Ion- carbenium-Oxonium yang distabilkan bentuk mesomeri.

22 prof. aza21  R. Kieffer: Morfin dengan kaliumhexacyanoferat(III) teroksidasi menjadi pseudomorfin (2,2’- dehidrodimorfin), Hexacyanoferat(II) yang terbentuk dengan FeCl 3 akan bewarna biru berlin.  R.Zimmermann: Hidromorfon, Hidrocodon dan, C-7 metilen yang diaktivasi karbonil akan bereaksi dengan m- dinitrobenzen membentuk senyawa Zimmermann yang bewarna

23 prof. aza22 R. Identifikasi  R. Deniges : Morfin + H 2 O 2, + amoniak encer + lrt CuSO 4, terbentuk warna merah, spesifik untuk morfin.  Cod fospat, +H 2 O4, + lrt FeCl 3, terjadi pemutusan eter membentuk apomorfin sebagai suatu fenol akan menjadi biru, + HNO 3 berubah jadi merah.  Heroin :dng Marquis merah violet; dipanaskan dgn H 2 SO 4 dl etanol terbentuk etilasetat(bau spesifik) dan morfin yang dapat diidentifikasi dengan P. Kieffer.

24 prof. aza23 Analgetika dan antitusif gol. Morfinan dan benzomorfan  Grewe (1946) mengsintesis morfinan, beda dengan morfin, tidak ada jembatan eter.  Pada trisiklik 5,9-dimetil-benzomorfan, sisa cincin-C tinggal 2-metil.  Levorphanol potensi analgetika melebihi morfin. Dextrophan bentuk dektro leforphanol tidak punya efek analgetik, tapi antitusif.  Dextrometorphan adalah metileter dextrophan, antitusif.  Pentazocin, potensi analetik 1/3 morfin, juga punya efek antagonis morfin yang lemah (tidak termasuk daftar O).

25 prof. aza24 SAR morfinan dan benzomorfan  Walau morfinan dan 5,9- dimetilbenzomorfan punya 3C khiral, tetapi isomer bukan 2 3, karena cincin piperidin dan cincin-C hanya berhubungan secara cis.  Morphinan berdasarkan ikatan cincin B/C: kalau cis ((+) dan (–)-morfinan), kalau trans ((+) dan (–)pseudomorfinan); (-)-morfinan konfigurasi seperti morfin alami.  Benzomorfan, berdasarkan substitusi pada cincin B: pada derivat  : C-5 dan C-9 cis, sedangkan pada derivat  trans

26 prof. aza25

27 prof. aza26

28 prof. aza27 Dari tabel dapat dilihat, bahwa derivat  mempunyai potensi analgetik yang lebih kuat dibanding derivat , dan bentuk (-) juga lebih kuat dibanding bentuk (+).

29 prof. aza28 Morfin antagonis  Efek antagonis ditemui pada derivat morfin, dihidromorfin dan morfinan, yang digunakan dalam pengobatan adalah nalorfin, naloxon dan levallorphan.  Antagonis menghilangkan efek sentral dan perifer dari opiat, terutama mengangkat depresi pernafasan, menghilangkan efek negatif pada morfinis.  Naloxon antagonis murni, nalorfin antagonis parsial.

30 prof. aza29 SAR-morfin antagonis  Pada analgetika derivat morfin, morfinan dan benzomorfan, penggantian sisa N-metil dengan substitusi 3-5 atom C, sering berubah menjadi senyawa antagonis kuat.  Substituen yang paling potensial adalah sisa alil.  makin kuat efek morfinik senyawa awal, makin kuat efek antagonis senyawa yang terbentuk.

31 prof. aza30

32 prof. aza31 Analgetika phetidin dan turunannya Phetidin disintesis oleh Eisleb dengan tujuan mendapatkan senyawa dengan aktivitas spasmolitik atropin, uji farmakologi dilakukan oleh Schaumann, ternyata disamping memiliki efek spasmolitik atropin, senyawa juga menunjukkan efek analgetik-morfin. Phetidin disintesis oleh Eisleb dengan tujuan mendapatkan senyawa dengan aktivitas spasmolitik atropin, uji farmakologi dilakukan oleh Schaumann, ternyata disamping memiliki efek spasmolitik atropin, senyawa juga menunjukkan efek analgetik-morfin. Pada 1939 pertama kali dipasarkan senyawa analgetika opiat yang disintesis secara total. Pada 1939 pertama kali dipasarkan senyawa analgetika opiat yang disintesis secara total.

33 prof. aza32 Phetidin adalah derivat 4-fenil-piperidin yang mempunyai persamaan cincin A dan D dengan morfin. Kedua senyawa juga mempunyai atom C-kuartener. Pethidin mempunyai aktivitas analgetika lebih lemah dibanding morfin juga efek samping yang lebih ringan, adanya aktivitas spasmolitik menguntungkan untuk mengatasi kolik. Cetobemidon, analgetika lbh kuat dibanding morfin, bahaya adiksi juga lebih besar.

34 prof. aza33   Phetidin adalah derivat 4-fenil-piperidin yang mempunyai persamaan cincin A dan D dengan morfin.   Kedua senyawa juga mempunyai atom C-kuartener.   Pethidin mempunyai aktivitas analgetika lebih lemah dibanding morfin juga efek samping yang lebih ringan, adanya aktivitas spasmolitik menguntungkan untuk mengatasi kolik.   Cetobemidon, analgetika lbh kuat dibanding morfin, bahaya adiksi juga lebih besar.

35 prof. aza34 Golongan Pethidin

36 prof. aza35 SAR-Pethidin dan Derivat  Gugus ester –COOC 2 H 5 dapat ditukar dengan inversi ester –O-CO-C 2 H 5 (alphaprodin) dan beberapa gugus mengandung Oksigen lainnya, tanpa kehilangan efek analgetiknya.  Substitusi pada sisa 4-fenil akan menghilangkan aktivitas, kecuali gugus hidroksil seperti pada Cetobemidon.  N-metil dapat divarisikan secara terbatas. Penggantian dengan H atau alkil yang lebih kecil mengurangi aktivitas, sedang alkil yang kebih komplek meningkatkan aktivitas.  Pergeseran ester dan sisa fenil dari posisi-4 akan menghilangkan atau mengurangi aktivitas.  Penambahan satu metilen pada cincin piperidin masih mungkin, tapi efek optimal diberikan oleh cincin-6.

37 prof. aza36 Sintesis Pethidin

38 prof. aza37 Analgetika dan antitusif methadon derivat  Bockmull dan Ehrkhart (1941) mengsintesis derifat senyawa difenilmetana bersubstitusi basa, uji farmakologi dilakukan oleh Schaumann. Di gunakan dl pengobatan bentuk levomethadon (Konfigurasi-R).  Methadon aktivitas analgetik lebih kuat dibanding morfin.  Normethadon memiliki aktivitas antitusif.  Dextropropoxyphen, homolog difenilmetan, potensi analgetiknya setara codein.

39 prof. aza38 Mempunyai kesamaan dengan struktur morfin dengan adanya C-kuartener yang melalui jembatan C-C dihubungkan dengan N-tersier. Dan adanya substitusi fenil pada C-kuartener.

40 prof. aza39

41 prof. aza40 Sintesis methadon

42 prof. aza41 Analgetika kuat, Struktur parsial yang esential  Atom C sentral, tidak memegang H  Sisa aromatik pada C sentral  Gugus amin tersier  Jarak 2 C dari C- sentral ke amin tersier (kecuali pada Tilidin).

43 prof. aza42 Fentanyl, N-[1-(2-phenyl-ethyl)piperidinyl]- propionanilid, analgetika morfinik, potensi 80x morfin. N-acyl ekivalen dengan C sentral

44 prof. aza43 Struktur ligand analgetika morfinik  Cincin A (hidroksifenil) dan hidroksifenil tyrosin pada enkephalin  Amin tersier morfin dan gugus amino tyrosin pada enkephalin.  Sisa fenilalkil pada PET dan fenilalanin pada enkephalin.

45 Tambahan Informasi prof. aza44

46 prof. aza45

47 prof. aza46 Opioid Receptors  Opioid receptors are a group of G-protein coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins and endorphins. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). G-protein coupled receptorsopioidsligandsendogenousopioidsdynorphins enkephalinsendorphins somatostatinreceptorsG-protein coupled receptorsopioidsligandsendogenousopioidsdynorphins enkephalinsendorphins somatostatinreceptors  1. Types of receptors

48 prof. aza47 Opioid Receptors  There are three major subtypes of opioid receptors: μ (mu), κ (kappa), and δ (delta). The receptors were named using the first letter of the first ligand that was found to bind to them. Morphine was the first chemical shown to bind to mu receptors. The first letter of the drug morphine is `m'. But in biochemistry there is a tendency to use Greek letters so they converted the 'm' to μ. Similarly a drug known as Ketocyclazocine was first shown to attach itself to kappa receptors.An alternative classification system is based on their order of discovery the receptors being termed OP1 (δ), OP2 (κ), and OP3 (μ). ligand Morphine Ketocyclazocineligand Morphine Ketocyclazocine

49 prof. aza48 Opioid Receptors  The opioid receptor types are ~70% identical with differences located at N and C termini. The μ receptor (the μ represents morphine) is perhaps the most important. It is thought that the G protein binds to the third intracellular loop of the opioid receptors. Both in mice and humans the genes for the various receptor subtypes are located on different chromosomes. G proteinmicehumans G proteinmicehumans  Separate subtypes (μ1, μ2; κ1, κ2, κ3; δ1, δ2) have been identified in human tissue. Research has so far failed to identify the genetic evidence of the subtypes, and it is thought that they arise from post-translational modification of cloned receptor types (Fries, 2002). post-translational modificationpost-translational modification

50 prof. aza49 The μ-opioid receptor  The μ opioid receptors (MOR) can exist either presynaptically or postsynaptically depending upon cell types. MOR can mediate acute changes in neuronal excitability via "disinhibition" of presynaptic release of GABA (see works from Charles Chavkin and Roger Nicoll)

51 prof. aza50 The μ-opioid receptor  In contrast, chronic activation of MOR causes the collapse of dendritic spines via post-synaptic mechanisms (see works from Dezhi Liao and Horace Loh).  The physiological and pathological roles of these two distinct mechanisms remain to be clarified. Perhaps, both might be involved in opioid addiction and opioid- induced deficits in cognition.

52 prof. aza51  The μ-receptors exist mostly presynaptically in the periaqueductal gray region, and in the superficial dorsal horn of the spinal cord. Other areas where μ-receptors have been located include the external plexiform layer of the olfactory bulb, the nucleus accumbens, in several layers of the cerebral cortex and in some of the nuclei of the amygdala. presynapticallyspinal cord olfactory bulbnucleus accumbensnucleiamygdalapresynapticallyspinal cord olfactory bulbnucleus accumbensnucleiamygdala  The μ-receptor has high affinity for enkephalins and beta-endorphin but low affinity for dynorphins. The opioid alkaloids morphine and codeine are known to bind to this receptor. alkaloids

53 prof. aza52 The κ-opioid receptor  κ-Opioid receptors are also involved with analgesia, but activation also produces marked nausea and dysphoria. Kappa ligands are also known for their characteristic diuretic effects, due to their negative regulation of anti diuretic hormone(ADH). dysphoria  Kappa agonism is neuroprotective against hypoxia\ischemia, as such, kappa receptors may represent a novel therapeutic target. The endogenous ligands for the Kappa receptor are the dynorphins. κ receptors are located in the periphery by pain neurons, in the spinal cord and in the brain.

54 prof. aza53 The κ-opioid receptor  Kappa agonists whether full or partial produce psychotomimetic effects. In the case of the mixed (partial) agonist/antagonist analgesic drugs e.g. butorphanol, nalbuphine and buprenorphine the psychotomimesis is undesirable and serves to limit abuse potential. In the case of Salvinorin A, a structuraly novel neoclerodane diterpene Kappa ligand, these effects are sought after. butorphanolnalbuphine buprenorphineSalvinorin Abutorphanolnalbuphine buprenorphineSalvinorin A  While Salvinorin A is considered a hallucinogen by those to whom it is known, its effects are qualitatively different than those produced by the classical indoleamine hallucinogens.

55 prof. aza54 The δ-opioid receptor  δ-Opioid receptor activation also produces analgesia. Some research suggests that they may also be related to seizures.  The endogenous ligands for the δ receptor are the enkephalins. Until quite recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors.

56 prof. aza55 The δ-opioid receptor, continued  Recent work indicates that exogenous ligands which activate the delta receptors mimic the phenomenon known as 'ischemic preconditioning'. Experimentally, if short periods of transient ischemia are induced the downstream tissues are robustly protected if permanent interruption of the blood supply is then effected. Opiates and opioids with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection

57 prof. aza56 The σ receptor  The sigma receptors σ1 and σ2 were once thought to be a type of opioid receptor, because the d stereoisomers of the benzomorphan class of opioid drugs had no effects at μ, κ, and δ receptors, but reduced coughing. σ1σ2σ1σ2  However, pharmacological testing indicated that the sigma receptors were activated by drugs completely unrelated to the opioids, and their function was unrelated to the function of the opioid receptors.

58 prof. aza57 The σ receptor, continued  For example, phencyclidine (PCP), and the antipsychotic haloperidol may interact with these receptors. Neither phencyclidine nor haloperidol have any appreciable chemical similarity to the opioids.  When the σ1 receptor was isolated and cloned, it was found to have no structural similarity to the opioid receptors. At this point, they were designated as a separate class of receptors. The functions of these receptors are poorly understood and any endogenous ligands have yet to be identified

59 prof. aza58 The orphan opioid receptor (ORL 1)  An additional opioid receptor has been identified and cloned based on homology with the cDNA. This receptor is known as the ORL 1 receptor. Its natural ligand is known alternately as nociceptin or orphanin. cDNA  Nociceptin is thought to be an endogenous antagonist of dopamine transport that may act either directly on dopamine or by inhibiting GABA to effect dopamine levels. Within the central nervous system its action can be either similar or opposite to those of opioids depending on their location. dopamine GABA central nervous systemdopamine GABA central nervous system

60 prof. aza59 The orphan opioid receptor (ORL 1)  It controls a wide range of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. nociception memorycardiovascularrenallocomotor activitygastrointestinalanxietyneurotransmitternociception memorycardiovascularrenallocomotor activitygastrointestinalanxietyneurotransmitter  ORL 1 agonists are being studied as treatments for heart failure and migraine while nociceptin antagonists may have antidepressant qualities. The novel drug buprenorphine is a partial agonist at ORL 1 receptors while its metabolite norbuprenorphine is a full agonist at these receptors (7). agonists antagonistsbuprenorphine norbuprenorphineagonists antagonistsbuprenorphine norbuprenorphine

61 prof. aza60 Enkephalins  Properties of Enkephalins How it all begins

62 prof. aza61 Enkephlain  Pro-enkephlain A is comprised of 91 amino acids. The peptide contains mostly cysteine residues to form disulfide bridges, and help protect against degradation. The following darkened areas are met- enkaphalin, and leu-enkaphalin.  [3 to 4 met-enkephalins for every leu-enkephalin].  The individual enkephalins are cleaved by endopeptidases

63 prof. aza62 Amino Acid Structure Differentiating characteristics are on the C- terminus.Differentiating characteristics are on the C- terminus. Amino acids that are crucial to its function are Tyr1, Gly3, and Phe4Amino acids that are crucial to its function are Tyr1, Gly3, and Phe4 Amino acids 1-4 are highly conserved, and the 5th can be varied.Amino acids 1-4 are highly conserved, and the 5th can be varied. If Tyrosine is hydrolyzed, the peptide is non- functional.If Tyrosine is hydrolyzed, the peptide is non- functional. The peptide binds easily to the delta region of the receptor.The peptide binds easily to the delta region of the receptor. When the chain length is lengthened after Phe, the binding affinity gets stronger.When the chain length is lengthened after Phe, the binding affinity gets stronger.

64 prof. aza63 Where do Enkephalins come from?  Enkephalins are secreted in the brain, mainly from the hypothalamus  In this image taken from a rat brain, one can clearly see how enkephalins are much more abundant and widespread throughout the brain than endorphins..

65 prof. aza64  Enkaphalins have numerous functions, however it is very hard for researchers to track them in the body due to their extremely small size.  Another factor that is limiting in the amount of research that can be done is the fact that in order to track the peptide, a huge globular, highly recognizable structure must be attached as a marker. This may give false implications of what actually happens in vivo

66 prof. aza65 Structure of a met- enkephalin (one conformation)

67 prof. aza66 Structure of a met-enkephalin Found to have a preferred conformation rather than a random coil. A Beta-pleated sheet held together by intermolecular NH-CO hydrogen bonds.Found to have a preferred conformation rather than a random coil. A Beta-pleated sheet held together by intermolecular NH-CO hydrogen bonds. Data studies using the NMR suggest that the hydrogen bonding from the H on the methionine and the O on the Gly, form the B-fold.Data studies using the NMR suggest that the hydrogen bonding from the H on the methionine and the O on the Gly, form the B-fold. The terminal NH3 group is highly shielded by the hydrophobic side chains of the peptide.The terminal NH3 group is highly shielded by the hydrophobic side chains of the peptide. Amino acid side chains are oriented above and below the plane of the molecule. This makes the molecule asymmetrical.Amino acid side chains are oriented above and below the plane of the molecule. This makes the molecule asymmetrical. Charge-Charge dipole between Oxygens and terminal NH3 also helps stabilize the structure.Charge-Charge dipole between Oxygens and terminal NH3 also helps stabilize the structure.

68 prof. aza67 How the neurotransmitter binds to the receptor How the neurotransmitter binds to the receptor This is a schematic illustration of the interactions of enkephalins with opioid receptor sites. Notice the rings from Tyr1 and Phe4 are what the receptor recognizes. This is a schematic illustration of the interactions of enkephalins with opioid receptor sites. Notice the rings from Tyr1 and Phe4 are what the receptor recognizes. Sites T and P are opioid receptor sites Sites T and P are opioid receptor sites Site A is the anionic site paired with the protonated Nitrogen of the opioids. Site A is the anionic site paired with the protonated Nitrogen of the opioids. Group G on subsite T represents a hydrogen-bonding acceptor dipole. Group G on subsite T represents a hydrogen-bonding acceptor dipole.


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