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Edit Comment Close Premium member Presentation Transcript Ion Channels: Molecular Target for the Development of Newer Anthelmintics : Ion Channels: Molecular Target for the Development of Newer Anthelmintics P. K. Verma Assistant Professor Division of Pharmacology and Toxicology Faculty of Veterinary Sciences and Animal Husbandry SKUAST- J, R.S. Pura. Jammu (J & K) Why newer anthelmintics ? : Why newer anthelmintics ? Currently available anthelmintics; Poor efficacy & non-selectivity to parasites, Development of drug resistance, High cost and less availability, Adverse reactions & residual toxicity in the host tissues Slide 3: Target Identification Target Validation Lead Identification Lead Optimization Target discovery Lead discovery Phases of a drug development Clinical Phases (I-III) 28 million ligands currently known Few selected ligands as potential drugs Approximantely 50,000 ligand molecules for the anthelmintics Slide 4: Adult worms do not multiply in the mammalian host. The most effective chemotherapeutic targets have been: Energy metabolism Muscular activity Selective target sites identification Muscular activity of parasites : Muscular activity of parasites Worms have complex neuromuscular system and is important for site identification because proper functioning of neuromuscular system obligatory for migration, attachment, feeding, egg laying and several other vital functions of the helminth parasites. Neuromuscular system ↔ neurotransmitters /neuropeptide ↔ ion channels. Ion Channels : Ion Channels Ion channels are the trans-membrane protein molecules located in the nerve membrane or at neuromuscular junction. An agonist causes the channel to open and allows specific ions to across the cell membrane. A number of important anthelmintics like, ivermectin, Levamisole, piperazine, pyrantel, praziquantel, milbemycin and organo-phosphorus anthelmintics etc. influencing activity of ion channels Ion Channels : Ion Channels Voltage gated ion channels Ligand gated ion channels Ion channels : Ion channels The ion channels are of following type Sodium Channels Calcium Channels Chloride channels Potassium channels Slide 9: Slide 10: Molecular model Structural units These receptor proteins are isolated immuno-cytochemically and functionally in different helminths and in most of parasites have similar function as in the mammals Na+ Channels (Nicotinic receptors) Nicotinic receptors : Nicotinic receptors Acetylcholine and agonists like, nicotine, carbachol produces inhibitory effect (spastic paralysis) on the neuromuscular activity in F. hepatica, F. gigantica, S. mansoni, G. crumenifer and Bdelloura candida. Atropine, cholinergic receptor antagonist has been shown to stimulate the rhythmic activity of S. mansoni, F. hepatica, F. gigantica. Slide 12: The acetyl-cholinesterase inhibitors like neostigmine and metrifonate cause a spastic paralysis of S. mansoni. Atropine antagonized paralytic effect of carbachol in dose-dependent manner on S. mansoni . Pyrental/ morental produces spastic paralysis of facilitating the action of ACh by inhibiting the activity of acetyl-cholinesterase. Ca++ Channels : Ca++ Channels Muscular activity in parasites : Muscular activity in parasites Ca++ ions free bathing medium >> reduces Calcium channel blockers >> reduces Calcium-dependent induced contractions have been observed in dispersed muscle fibres of Schistoma mansoni. Praziquantel : Praziquantel Ligand -gated Ca++ channels consist of α1 and β subunits Schistosomes - two subtypes of β subunit: a conventional subtype similar to β subunits found in all organism. and a novel variant subtype β subunit present in the schistosome. The binding site for praziquantel is present on variant schistosome β subunit whereas, mammalian Ca++ channels are praziquantel-insensitive. Receptors and Ca++ movements : Receptors and Ca++ movements ATP-gated P2X receptor Cloned and expressed from S. mansoni (Agboh et al., 2004) N-methyl D-aspartate (NMDA) receptors Longitudinal muscle fibres isolated from S. mansoni (Miller et al., 1996) and Hymenolepis diminuta (Thompson and Mettrick, 1989) Tryptaminergic receptors Serotonin induced Ca ++ dependent contraction (Bennett & Pax, 1994) FMRF amide-related peptides Muscle fibers from S. mansoni (Day et al., 1994) Slide 18: Pharmacological experiments and radioactive binding are suggestive of presence of inositol-1, 4, 5-triphosphate (IP3) and ryanodine receptors are in schistosomes and other flatworms (Day et al., 2000). Chloride Channels : Chloride Channels In mammals, chloride ions facilitate inhibitory (flaccid paralysis) action on cellular activity Chloride ions facilitation occur primarily through GABA receptors GABA is an important inhibitory neurotransmitter of parasitic flatworm (Eriksson et al., 1995). GABA in parasites : GABA in parasites GABA is shown immuno-cytochemically in Moneizia expansa, Fasciola hepatica, Hymenolepis diminuta and Schistosoma mansoni and Functionally in F. gigantica and G. crumenifer GABAergic receptors : GABAergic receptors GABA glutamate glucose Cl- GABAergic receptors : GABAergic receptors Receptors GABAA receptors GABAB receptors In most of the helminths parasites the receptor protein isolated have structural and functional similarity with GABAA receptors Slide 23: GABAA Receptor Cl- GABAA receptor : GABAA receptor A. suum, activation of GABA receptors caused inhibition of muscular activity by increasing Cl- conductance (Holden-Dye et al., 1989). Whereas in Dicrocoelium dendriticum, different GABA binding proteins have been demonstrated (Gimenez-Pardo et al., 2000). These receptors were bicuculline insensitive and picrotoxin sensitive and have more similarity with vertebrate GABAA receptor subtypes in A. suum and G. crumenifer (Bascal et al., 1995, Verma, 2003). Glutamate-gated chloride channels (GluCl): : Glutamate-gated chloride channels (GluCl): These receptors facilitates Cl- ion conductance and facilitate inhibitory cellular action (flaccid paralysis) Glutamate-gated chloride channels receptors and are the target sites for the ivermectin / milbemycin anthelmintics Haemonchus contortus muscles four subtypes of GluCl channels are identified i.e. HcGluClalpha, HcGluClbeta, HcGluClalpha3A, and HcGluClalpha3B (Portillo et al., 2003). Slide 26: Schematic representation of the invertebrate and vertebrate chloride ion channels under ivermectin control Slide 27: Ion channels are the important site for identifying the newer target for drug action. Agonistic and antagonistic interaction studies suggest the functional differences between receptor proteins of mammals and parasites. Modern techniques for isolation and purification of receptor proteins help in determine the structural differences with mammals. Identification of functional and structural differences may be the selective target for the newer anthelmintics Slide 28: THANKS You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.
ion channels-as drug target drpawankv Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: (To copy code, click on the text box) Embed: URL: Thumbnail: WordPress Embed Customize Embed The presentation is successfully added In Your Favorites. Views: 787 Category: Science & Tech.. License: All Rights Reserved Like it (4) Dislike it (0) Added: December 05, 2009 This Presentation is Public Favorites: 1 Presentation Description No description available. Comments Posting comment... By: drpawankv (21 month(s) ago) send the mail id i attach the ppt through return mail drpawankv@yahoo.co.in Saving..... Post Reply Close Saving..... Edit Comment Close By: swetajha (21 month(s) ago) pl tell me how i can download it.... this ppt is really nice. Saving..... Post Reply Close Saving..... Edit Comment Close Premium member Presentation Transcript Ion Channels: Molecular Target for the Development of Newer Anthelmintics : Ion Channels: Molecular Target for the Development of Newer Anthelmintics P. K. Verma Assistant Professor Division of Pharmacology and Toxicology Faculty of Veterinary Sciences and Animal Husbandry SKUAST- J, R.S. Pura. Jammu (J & K) Why newer anthelmintics ? : Why newer anthelmintics ? Currently available anthelmintics; Poor efficacy & non-selectivity to parasites, Development of drug resistance, High cost and less availability, Adverse reactions & residual toxicity in the host tissues Slide 3: Target Identification Target Validation Lead Identification Lead Optimization Target discovery Lead discovery Phases of a drug development Clinical Phases (I-III) 28 million ligands currently known Few selected ligands as potential drugs Approximantely 50,000 ligand molecules for the anthelmintics Slide 4: Adult worms do not multiply in the mammalian host. The most effective chemotherapeutic targets have been: Energy metabolism Muscular activity Selective target sites identification Muscular activity of parasites : Muscular activity of parasites Worms have complex neuromuscular system and is important for site identification because proper functioning of neuromuscular system obligatory for migration, attachment, feeding, egg laying and several other vital functions of the helminth parasites. Neuromuscular system ↔ neurotransmitters /neuropeptide ↔ ion channels. Ion Channels : Ion Channels Ion channels are the trans-membrane protein molecules located in the nerve membrane or at neuromuscular junction. An agonist causes the channel to open and allows specific ions to across the cell membrane. A number of important anthelmintics like, ivermectin, Levamisole, piperazine, pyrantel, praziquantel, milbemycin and organo-phosphorus anthelmintics etc. influencing activity of ion channels Ion Channels : Ion Channels Voltage gated ion channels Ligand gated ion channels Ion channels : Ion channels The ion channels are of following type Sodium Channels Calcium Channels Chloride channels Potassium channels Slide 9: Slide 10: Molecular model Structural units These receptor proteins are isolated immuno-cytochemically and functionally in different helminths and in most of parasites have similar function as in the mammals Na+ Channels (Nicotinic receptors) Nicotinic receptors : Nicotinic receptors Acetylcholine and agonists like, nicotine, carbachol produces inhibitory effect (spastic paralysis) on the neuromuscular activity in F. hepatica, F. gigantica, S. mansoni, G. crumenifer and Bdelloura candida. Atropine, cholinergic receptor antagonist has been shown to stimulate the rhythmic activity of S. mansoni, F. hepatica, F. gigantica. Slide 12: The acetyl-cholinesterase inhibitors like neostigmine and metrifonate cause a spastic paralysis of S. mansoni. Atropine antagonized paralytic effect of carbachol in dose-dependent manner on S. mansoni . Pyrental/ morental produces spastic paralysis of facilitating the action of ACh by inhibiting the activity of acetyl-cholinesterase. Ca++ Channels : Ca++ Channels Muscular activity in parasites : Muscular activity in parasites Ca++ ions free bathing medium >> reduces Calcium channel blockers >> reduces Calcium-dependent induced contractions have been observed in dispersed muscle fibres of Schistoma mansoni. Praziquantel : Praziquantel Ligand -gated Ca++ channels consist of α1 and β subunits Schistosomes - two subtypes of β subunit: a conventional subtype similar to β subunits found in all organism. and a novel variant subtype β subunit present in the schistosome. The binding site for praziquantel is present on variant schistosome β subunit whereas, mammalian Ca++ channels are praziquantel-insensitive. Receptors and Ca++ movements : Receptors and Ca++ movements ATP-gated P2X receptor Cloned and expressed from S. mansoni (Agboh et al., 2004) N-methyl D-aspartate (NMDA) receptors Longitudinal muscle fibres isolated from S. mansoni (Miller et al., 1996) and Hymenolepis diminuta (Thompson and Mettrick, 1989) Tryptaminergic receptors Serotonin induced Ca ++ dependent contraction (Bennett & Pax, 1994) FMRF amide-related peptides Muscle fibers from S. mansoni (Day et al., 1994) Slide 18: Pharmacological experiments and radioactive binding are suggestive of presence of inositol-1, 4, 5-triphosphate (IP3) and ryanodine receptors are in schistosomes and other flatworms (Day et al., 2000). Chloride Channels : Chloride Channels In mammals, chloride ions facilitate inhibitory (flaccid paralysis) action on cellular activity Chloride ions facilitation occur primarily through GABA receptors GABA is an important inhibitory neurotransmitter of parasitic flatworm (Eriksson et al., 1995). GABA in parasites : GABA in parasites GABA is shown immuno-cytochemically in Moneizia expansa, Fasciola hepatica, Hymenolepis diminuta and Schistosoma mansoni and Functionally in F. gigantica and G. crumenifer GABAergic receptors : GABAergic receptors GABA glutamate glucose Cl- GABAergic receptors : GABAergic receptors Receptors GABAA receptors GABAB receptors In most of the helminths parasites the receptor protein isolated have structural and functional similarity with GABAA receptors Slide 23: GABAA Receptor Cl- GABAA receptor : GABAA receptor A. suum, activation of GABA receptors caused inhibition of muscular activity by increasing Cl- conductance (Holden-Dye et al., 1989). Whereas in Dicrocoelium dendriticum, different GABA binding proteins have been demonstrated (Gimenez-Pardo et al., 2000). These receptors were bicuculline insensitive and picrotoxin sensitive and have more similarity with vertebrate GABAA receptor subtypes in A. suum and G. crumenifer (Bascal et al., 1995, Verma, 2003). Glutamate-gated chloride channels (GluCl): : Glutamate-gated chloride channels (GluCl): These receptors facilitates Cl- ion conductance and facilitate inhibitory cellular action (flaccid paralysis) Glutamate-gated chloride channels receptors and are the target sites for the ivermectin / milbemycin anthelmintics Haemonchus contortus muscles four subtypes of GluCl channels are identified i.e. HcGluClalpha, HcGluClbeta, HcGluClalpha3A, and HcGluClalpha3B (Portillo et al., 2003). Slide 26: Schematic representation of the invertebrate and vertebrate chloride ion channels under ivermectin control Slide 27: Ion channels are the important site for identifying the newer target for drug action. Agonistic and antagonistic interaction studies suggest the functional differences between receptor proteins of mammals and parasites. Modern techniques for isolation and purification of receptor proteins help in determine the structural differences with mammals. Identification of functional and structural differences may be the selective target for the newer anthelmintics Slide 28: THANKS