There are many G-protein coupled receptors and one of the major categories for neurological drug development are called muscarinic receptors because they were first known to be activated by a mushroom alkaloid called muscarine. The isolation and characterization of muscarine was first reported by chemists in 1869! Muscarine works by mimicking the neurotransmitter acteylcholine on the receptors.
The receptors are interesting too.
There are 5 main subtypes called M1, M2, M3, M4, M5
The M2 and M3: peripheral autonomic tissues
M1 and M4 subtype are in brain and autonomic ganglia.
M1, M3, M5 (Excitatory)– interact with Gq within the cell to stimulate phosphoinositide hydrolysis releasing calcium
M2 and M4 (Inhibitory): interact with Gi proteins to inhibit adenylyl cyclase decreasing cAMP.
M1 – High levels in cortex and hippocampus and important for learning and memory
M2 – Predominant in the heart, slows heart rate
M3 – Found in smooth muscle (bladder, lungs, eyes), muscle contraction and secretion
M4 – Present in striatum regulates movement and dopamine levels
M5 – Midbrain and used in dopamine releasing and blood vessel dilation in the brain
There are three kinds of drugs that target the receptors:
- Activators: Bethenecol (Urinary retention), Pilocarpin (Glaucoma) and Xanomeline(schizophrenia psychosis)1
2. Antagonists: Ipratropium (COPD and asthma), Oxybutynin (Overactive bladder)
3. Cholinsterase inhibitors: Donepezil (Alzheimer’s) and pyrdostigmine (improve muscle strength)
The biology is complex and there are many drugs that bind to specific receptors but also serve as allosteric modulators that enhance the effect of acetylcholine binding (Positive allosteric modulator) or decrease the effect of acetylcholine binding (Negative allosteric modulator)
To block the receptor one drug that is used is Atropine. This inhibits the effect of muscarine by binding and blocking the muscarinic receptors and inhibits acetylcholine too…It relaxes the ciliary muscle and used in the treatment of glaucoma.
