Curare Alkaloids.pptx

Curare alkaloids, Natural products

1. Presenation on Curare Alkaloids PRESENTED BY: Mr. Abhimanyu Awasthi I M. Pharm ( Pharmaceutical Chemistry ) Dept. Of Chemistry JSS College of Pharmacy, Mysore PRESENTED TO: Dr. G.V Pujar sir Vice Principal & Professor , JSS College of Pharmacy, Mysore Chemistry of Natural Products

2. History & Discovery of Curare Alkaloids Curare was used for centuries by South American Indians to hunt game, and its evolution into the designer drugs of today began when tales of the mysterious ‘flying death’ were brought home to the Old World by Spanish conquistadors. Peter Martyr d'Anghera, a chronicler in the Court of King Ferdinand and Queen Isabella, first wrote of the poisoned arrows in his book De Orbe Novo, a collection of letters written in 1516 . The best known and historically most important (because of its medical applications) toxin is d-tubocurarine. It was isolated from the crude drug - from a museum sample of curare - in 1935 by Harold King (1887–1956) of London, working in Sir Henry Dale’s laboratory. He also established its chemical structure. It was introduced into anesthesia in the early 1940s as a muscle relaxant for surger, Curare is active -toxic or muscle-relaxing, depending on the intended use - only by an injection or a direct wound contamination by poisoned dart or arrow. It is harmless if taken orally because curare compounds are too large and highly charged to pass through the lining of the digestive tract to be absorbed into the blood. In medicine, curare has been superseded by a number of curare-like agents, such as rocuronium, which have a similar pharmacodynamic profile but fewer side effects. Neuromuscular blocking drugs are often classified into two broad classes: Pachycurares , which are bulky molecules with nondepolarizing activity Leptocurares , which are thin and flexible molecules that tend to have depolarizing activity

3. Source of Curare Alkaloids T ubocurare (also known as tube or bamboo curare, because of its packing into hollow bamboo tubes; main toxin is D- T ubocurarine ) (DTC) . It is a mono-quaternary alkaloid, an isoquinoline derivative. calebas curare (also called "gourd curare" by older British classifications, being packed into hollow gourds; main toxins are alloferine and toxiferine) pot curare (packed in terra cotta pots; main toxins are protocurarine, protocurine, and protocuridine) . Pharmacological Action Curare is an example of a non-depolarizing muscle relaxant that blocks the nicotinic acetylcholin e receptor (nAChR), one of the two types of acetylcholine (ACh) receptors. The main toxin of curare, d-tubocurarine, occupies the same position on the receptor as ACh with an equal or greater affinity, and elicits no response, making it a competitive antagonist. The antidote for curare poisoning is an acetylcholinesterase (AChE) inhibitor (anti-cholinesterase), such as physostigmine or neostigmine. By blocking ACh degradation, AChE inhibitors raise the amount of ACh in the neuromuscular junction; the accumulated ACh will then correct for the effect of the curare by activating the receptors not blocked by toxin at a higher rate.

4. Pharmacodynamics of D-Tubocuarine (DTC) Tubocuraine is a Non-depolarizing Skeletal Muscle Relaxants (N 2 (inactive) Receptor Blockers). Each receptive site, in turn, has two subsites, namely, an anionic subsite to attract the positively charged onium head and a hydrogen bond donor to attract the hydrogen bond acceptor of Ach as shown in the above figure. The asymmetrical arrangement makes it possible for subsites of like charges to completely avoid facing each other directly. - HBD C ross-section at the level of the receptive sites (b–f). The pentameric rosette is arranged according to one version of Pedersen and Cohen. (a) Vertical section showing receptor dimensions and hypothetically a molecule of C10 between the receptive sites. (b) Each receptive site has an anionic subsite (A) and a hydrogen bond donor (H) subsite. The circular arrangement maximizes the chances for subsites of unlike charges to face each other and promote closure of the resting channel, shown in dashed lines. (c) Ionic channel opened by two Ach molecules. (d) Ionic channel opened by decamethonium binding both anionic subsites. (e) Blockage by vecuronium (flipped α side up) binding the anionic and the H bond donor subsites of one receptive site. (f) Blockage by a long-chain bisquaternary bulky NMB molecule that bends to fit between the anionic subsites.

5. Recent Advancement / SAR Studies D- T ubocurarine D-T ubocurarine (DTC) is a bis- benzylisoquinoline (BBIQ) derivative and shares this structural backbone with a number of plant-derived alkaloids, including morphine and papaverine. I ts structure, when first elucidated in 1948 was incorrectly thought to be bis-quaternary: in other words, it was thought to be an N,N-dimethylated alkaloid. In 1970, the correct structure was finally established,showing one of the two nitrogens to be tertiary, actually a mono-N-methylated alkaloid . The Presence of Quaternary Ammonium group targets the activity of Neuromuscular receptor Blockage. Papaverine

6. Recent Advancement / SAR Studies Two quaternary centres at specific separation (1.15nm) Tetrahydro isoquinoline derrivative Quaternary ammonium Tertiary amine i n acidosis ( + charge ) increase potency . Bis- quaternary ammonium compound having two quaternary ammonium salts separated by 10-12 carbon atoms was required for neuromuscular blocking activity . 1 -12 carbon bridge between 2 nitrogen max. Neuromuscular blockade . D- T ubocurarine as a Prototype

7. Suxamethonium (Succinyl Choline) Ester formation (Diester moeity) / Acts on autonomic ganglia. Mivacurium No Hoffman Elimination due to presence of Double bond Decamethonium Developed by King Harold by false assumption as bis-quatenary moeity. Atracurium Atracurium besylate (Organosulpphonate salt) Stable only in acidic pH Unstable in blood due to Hoffman Elimination. Analogues Derrivied from T ubocurarine as NMB.

8. Cogeners of Neuromuscular Blocking Agents Non Depolarizing Neuromuscular Blocking agent (Antagonist). Depolarzing NMB. (Agoinst) The two quaternary ammonium groups are separated by a bridging structure imparts lipophilic property. The Higher cogeners has been developed from Amino-Steroids having Steroidal Moeity. Highly Potent

9. Higher Cogeners of NM Blockers The Higher cogeners has been developed from Amino-Steroids having Steroidal Moeity. Steroid Skeleton act as a spacer for the quaternary centres (1.09nm) Acyl groups (R 2 ) are added to introduce the Ach skeleton. Faster onset than tubocurarine but slower than suxamethonium. Longer duration of action than suxamethonium (45 min).

10. Recent Advancement / SAR Studies

11. References Raghavendra, T. (2002). Neuromuscular blocking drugs: discovery and development. Journal of the Royal Society of Medicine, 95(7), 363-367. https://doi.org/10.1258/jrsm.95.7.363 e n.wikipedia.org/wiki/Neuromuscular-blocking_drug Utting JE. The era of relaxant anaesthesia. Br J Anaesth. 1992 Dec;69(6):551-3. [PubMed] King JM, Hunter JM. Physiology of the neuromuscular junction. BJA CEPD Rev 2002; 2: 129–33Crul JF. Relaxant drugs: from native drugs to the selective agents of today. Acta Anaesthesiol Scand. 1982 Aug;26(4):409-15. [PubMed] Samama P, Pei G, Costa T, Cotecchia S, Lefkowitz RJ. Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor. Mol Pharmacol. 1994 Mar;45(3):390-4. PMID: 7908404. Jonas Appiah-Ankam, MB ChB FRCA, Jennifer M Hunter, MB ChB PhD FRCA, Pharmacology of neuromuscular blocking drugs, Continuing Education in Anaesthesia Critical Care & Pain, Volume 4, Issue 1, February 2004, Pages 2–7

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