Cholinergic System Caro Flashcards
(27 cards)
The neurotransmitter of the parasympathetic nervous system
Acetylcholine (ACh)
Cholinergic and Cholinomimetic
Cholinergic
-neurons that release ACh and/or have receptors on which ACh synapses upon
Cholinomimetic
-Compounds that stimulate the parasympathetic nervous system
What are the two types of Cholinergic nerves?
Nicotinic
-ability to bind nicotine (ionotropic) Muscarinic
-ability to bind muscarine (metabotropic)
Muscarinic cholinergic agents
Compounds that interact with Muscarinic Acetylcholinergic Receptors (mAChR) used for:
-treat glaucoma
-treat cognitive disorders (Alzheimer’s)
-re-establish smooth muscle tone of the GI and urinary tract after surgery
Anticholinergic agents (mAChR antagonist)
Ability to reduce smooth muscle spasm
-used to treat overactive bladder
mAChR Stimulation
-leads to inhibition of adenylyl cyclase
-activation of phospholipase C (which generate secondary messengers)
What chemical structure should a cholinergic agent have?
A quaternary ammonium group (a ionic site) and a ester functional group (esteratic site)
Ing’s rule of 5
No more than 5 atoms between quaternary N and terminal H. (Esta regla no aplica a todo compuesto)
mAChRs subtypes and G-proteins interactions
-odd numbered mAChRs (M1, M3, M5) are coupled to with Gq protein (excitatory)
-even numbered mAChRs (M2 M4) are coupled to with Gi and Go proteins (Inhibitory)
Nicotinic Receptors (nAChRs)
-Found in neuromuscular junctions, adrenal medulla, and autonomic ganglia
-Play important role in myasthenia gravis
-Ionotropic that have two ACh binding sites which shows positive cooperativity
Acetylcholinesterase (AChE)
Break down ACh. Elimina el grupo Ester
Why can’t choline cross the Blood-Brain Barrier but its phosphate counterparts can?
Colina es muy soluble en agua por su carga, tamaño y logP. Para cruzar, se observar la estrategia de prodroga.
Which structure of ACh is more stable?
Antiperiplanar (trans)
Why is ACh not able to be administered orally?
ACh receptors are found in different organs and can interact with Nicotinic and Muscarinic receptors (no selectivity) causing uncontrollable activation to undesired receptors.
Muscarinic agonist SAR
Methacoline
-Metilacion en carbono beta
Carbachol
-presencia de un carbamato en el grupo Ester
Bethanchol
-Metilacion en carbono beta
-presencia de un carbamato en el grupo Ester
non-Specific Muscarinic Agonist
Miostat
-acts as an agonist to mAChRs and nAChRs
-Treatment of glaucoma and ocular surgery
-Carbamate este makes it less labios to hydrolysis (long duration)
Provocholine (methacholine chloride)
Specific Muscarinic agonist
-bronchial challenge test (diagnosis of asma)
-Metilacion en beta
Urecholine (bethanecol chloride)
Specific Muscarinic Agonist
-used for post-surgical
-orally administrated to avoid cholinergic crisis (sobre dosis)
-carbamato y Metilacion en beta
Salogen or Isopto Carpine (pilocarpene HCL)
Specific Muscarinic Agonist (M3)
-treat glaucoma and xerostomia
-hidrolisis por el Ester y no cumple regla de Ig
Evoxac (Cevimeline Hydrochloride)
Specific Muscarinic Agonist
-treat xerostomia
-quinuclidine derivative
-la presencia de azufre hace que se oxide
-Metabolizado por CYP
Acetylcholinesterase (AChE) inhibitors
Inhibe esta enzima por lo que se acumula ACh.
-improve muscle strength in myasthenia gravis and treat Alzheimer’s.
AChE Structure and Function
-Esteratic site = serine hydrylase (Ser, his, glu)
-Anionic site = N cation binds (Trp)
What happens when AChE is acylated?
It is inactive
Carbamylated AChE
Reversible AChE Inhibitors
-regeneration to an active AChE by hydrolysis is much slower
