Nicotinic and Muscarinic Drugs

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  • Created by: LBCW0502
  • Created on: 10-10-18 20:01
Which receptors and mechanisms are involved in the post synaptic neuron in the hypothetical cholinergic synapse?
Receptors are M4, M3, M5, M1 and the IP3 mechanism is involved (use of Na and Ca ions)
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Describe features of nicotinic receptors
Ligand gated ion channel, 5 sub units (alpha, beta, gamma, sigma, epsilon). Subunit combination determines ligand binding properties of the receptor, particularly antagonist binding
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What are the clinical targets for nicotinic drugs?
Cognitive performance, neurodegenerative diseases, Schizophrenia, anxiety and depression, Tourette's syndrome, epilepsy (nocturnal frontal lobe epilepsy), pain, smoking cessation, ulcerative colitis
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What are the challenges for designing nicotinic drugs?
The diversity of nAChRs, pharmacological differences between nAChR homologues of different species, heterologous expression of human recombinant nAChRs (particularly of receptors containing more than 2 different sub units (e.g. A6 beta4 beta3 alph5)
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Which molecules are used as templates for nicotinic drug design?
Nicotine, epibatidine and cytisine
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Describe features of nicotine as a template
Nicotine contains a tertiary amine - drug developments using nicotine have been unsuccessful
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Describe features of epibatidine as a template
Epibatidine contains a secondary amine with Cl, N and aromatic ring - drug developments using epibatidine have been unsuccessful
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Describe features of cytisine as a template
Drug developments using cytisine have been successful - contains aromatic ring with N, O and secondary amine
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What are the clinical applications of nicotinic agonists? (1)
Nicotine (full agonist of nicotinic receptors, all subtypes, used as smoking cessation aid). Varenicline (partial agonist of nicotinic receptor, used as smoking cessation aid). Suxamethonium (neuromuscular blocker, used as muscle relaxant)
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What are the clinical applications of nicotinic agonists? (2)
Galantamine (allosteric nicotinic receptor agonist, used in Alzheimer's disease)
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Nicotinic receptors are present in which system?
Somatic system
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Muscarinic receptors are present in which system?
Parasympathetic system
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What are the clinical applications of nicotinic antagonists? (1)
Hexamethonium (ganglionic NN receptor antagonist, no effect on muscarinic receptor, clinically discontinued due to ADRs). Trimetaphan (ganglionic NN receptor antagonist, limited used in pulmonary oedema and hypertension)
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What are the clinical applications of nicotinic antagonists? (2)
Pancuronium (competitive ACh antagonist at nicotinic NMJ, steroidal, muscle relaxant in anaethesia, lethal injections in USA). Atracurium (competitive ACh antagonist at nicotinic NMJ, non-steroidal, muscle relaxant in anaethesia)
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Describe the structure of muscarine
Contains a tertiary amine, OH, CH3 and non-aromatic ring groups
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Describe features of the muscarinic receptor
GCRP, can be orthosteric (one side), allosteric (in binding pocket) or bitopic (both side). Better affinity and subselectivity for bitopic
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Describe features of the muscarinic effect on the heart
ACh binding to M2 receptor leads to decreased cAMP. Decreased Ca entry leads to lower CO. Increased K efflux/hyperpolarisation leads to decreased heart rate
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Which M receptors are inhibitory?
M2 and M4
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Which M receptors are excitatory?
M1, M3 and M5
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Describe features of pilocarpine
Non-selective muscarinic agonist, in glaucoma it works on M3 receptor found in iris sphincter muscle, causes constriction of pupil, improves drainage of intraocular fluid via canals of Schlemm. t1/2 of 3-4 hrs, also used in dry mouth (xerostomia)
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What are the clinical applications of muscarinic agonists? (1)
Carbachol (non-selective muscarinic agonist, quaternary ammonium salt, not absorbed through GI, doesn't cross BBB, administered through ocular route). Xanomeline (selective M1/M4 receptor agonist, clinical trial in Schizophrenia)
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What are the clinical applications of muscarinic agonists? (2)
Cevimeline (selective M3 receptor agonist, used in dry mouth)
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What are the clinical applications of muscarinic antagonists?
Benztropine used for Parkinson's disease. Scopolamine used for motion sickness and to treat drug addition. Atropine produces mydriasis and cycloplegia, non-selective muscarinic antagonist
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Describe features of incontinence treatment with antimuscarinic agents
Oxybutinin - urinary incontinence, transient cystitis
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Describe features of the anti-secretory role of antimuscarinic agents
Ipratorium (as bronchodilator in asthma, COPD, lowers intracellular concentration of cGMP, local site specific effect). Methylscopoalmine - antiucler agent
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Describe features of the importance of the pharmacophore to develop agonist/antagonist
Establish which components are essential for activity e.g. ionic bonding, H bonding, weak interactions, covalent bonding (or else interactions are lost e.g. between agonist/antagonist and receptor)
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What is a pharmacophore?
Part of a drug molecule responsible for exerting a pharmacological effect
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What are the functional groups in ACh?
Tertiary amine, OH, methyl, C=O, OH
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Describe features of nicotinic vs muscarinic agents
Perform systematic variation in ligand conformation, compute potential energy of different conformers, compare low energy conformers, look for common features to identify pharmacophore
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What are the requirements for drug molecules to be muscarinic agonists?
Contain N and O with distance of 4.4. Angstrom
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What are the requirements for drug molecules to be nicotinic agonists?
N and N or N and O with distance of 5.9 Angstrom
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Can a drug molecule have a combination of features for nicotinic and muscarinic agonists?
Possible as long as the distances of 4.4 and 5.9 Angstrom are present
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Other cards in this set

Card 2

Front

Describe features of nicotinic receptors

Back

Ligand gated ion channel, 5 sub units (alpha, beta, gamma, sigma, epsilon). Subunit combination determines ligand binding properties of the receptor, particularly antagonist binding

Card 3

Front

What are the clinical targets for nicotinic drugs?

Back

Preview of the front of card 3

Card 4

Front

What are the challenges for designing nicotinic drugs?

Back

Preview of the front of card 4

Card 5

Front

Which molecules are used as templates for nicotinic drug design?

Back

Preview of the front of card 5
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