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Muscarinic acetylcholine receptor

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Lena Walton

on 14 May 2015

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Transcript of Muscarinic acetylcholine receptor

Complications faced when targeting the M1 receptor
Amino acid sequences are highly conserved among the orthosteric binding sites in the five mAChRs (Eglen, Guatam, Wess)
Non-selective targeting of the M1 receptor leads to several consequences
GI distress
Bradycardia (slow heart rate)
Experimental Evidence of mAChR's Value
J.J. Hagan, J.H. Jansen, C.L. Broekkamp (1987)
Muscarinic Acetylcholine Receptors (mAChR)
What is a mAChR?
Research in Alzheimer's Patients
Abnormal Activity and Alzheimer's Disease
Increasing Selectivity
Amino acid sequences are not conserved among the allosteric binding sites

Developed drugs that were allosteric agonists of the M1 receptor
used M1 mAChR antagonist to block M1's function in rats
rats showed
impaired cognitive ability
to memorize spatial map of maze
-Xanomeline is an m1 and m4 agonist
(similar to a ligand)

-effectively reduces out-bursts,
suspiciousness, delusions, agitation, and hallucinations in Alzheimer's patients

-gastrointestinal side effects caused a >50% discontinuation rate in clinical trials

m1 mAChR knockouts in mice
mice displayed a
deficit in attention
and
memory
inhibited long-term potentiation
(strengthing
of nerve impulses) in hippocampus

Anagnostaras et al. (2003)
Xanomeline's effect on mAChRs
C.J. Ladner, J.M. Lee (1999)
Possible Future Research
The Potential of BQCA
(Benzyl Quinolone Carboxylic Acid)
-specific allosteric agonist to solely the m1 subtype, reduces the amount of ACh needed for activiation

-most recent research is only trying to understand the relationship between BQCA chemical structure and its biological implications

-currently designing different BQCA analogues to see which one has increased effectiveness

-further research needed to see its effects on the future of Alzheimer's Disease
-no change in density of m1 mAChR
between Alzheimer's and control patients

-the number of mAChRs is not reduced, but
less mAChRs are in high-affinity binding state

-subthreshold levels of ACh to activate M1 subtype

-reduced functional capacity of M1 mAChR in Alzheimer's patients
N. C. Bodick et al. (1997)
Muscarinic acetylcholine receptors
Decreased acetylcholine (ACh) levels lead to decreased M1 pathway activation



Decreased sAPPα generation



Increased Aβ production

Plaques result in decreased cerebral blood flow


GPCR transmembrane proteins
highly expressed in the brain's hippocampus
related to memory and learning
Possible Future Research of BQCA
Increased α-secretase cleaves APP at the Aβ region to form sAPPα

Decreased neurotoxicity of Aβ

Counteracts effects of decreased cerebral blood flow
M1 mAChR: a drug target for alzheimer’s
Wild Type
Alzheimer's Disease
Alzheimer's
mAChRs in Alzheimer's Patients
Mirza, N. R., Peters, D. and Sparks, R. G. (2003)
Full transcript