Muscarinic agonists activity

The classic SAR for muscarinic agonist activity can be summarized as follows ... 

Rapid access to the chiral azabicyclo[2.2. Ijheptane backbone has been exploited in the synthesis of rigid enantiomorphic conformations (e.g. 75) of arecoline (74), a natural achiral alkaloid with muscarinic agonist activity [25] ... 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

Although ibogaine binds to muscarinic Ml and M2 receptors in the micromolar range, its action there is uncertain (Sweetnam et al. 1995). It fails to alter the adenylyl cyclase activity of a muscarinic agonist carbachol (Rabin and Winter 1996b). 

There are three ways to increase acetylcholine activity (1) increase the supply of acetylcholine, (2) directly stimulate acetylcholine receptors (muscarinic agonists), and (3) block the enzyme that inactivates acetylcholine (cholinesterase inhibitors). Let s take a look at each of these approaches. 

Muscarinic Agonists. Another approach is to use a medication that directly activates subtypes of the acetylcholine receptors, namely, muscarinic receptor agonists. The muscarinic agonists used in the past have not been effective. This includes bethanecol, pilocarpine, and oxotremorine. This line of treatment, however, has not been entirely abandoned, and several medications are currently in testing. 

Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings, from which the general notion that muscarinic agonists have parasympathomimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic receptors have a broader distribution and many functional roles. To understand the actions of cholinomimetic drugs it is essential to recognize that muscarinic receptors (1) mediate the activation of effectors by ACh released from parasympathetic nerve... 

SA node and A-V fibers become dominant. Activation of M2 receptors increases the potassium permeability and reduces cAMP levels, slowing the rate of depolarization and decreasing the excitability of SA node and A-V fiber cells. This results in marked bradycardia and a slowing of A-V conduction that can override the stimulation of the heart by catecholamines released during sympathetic stimulation. In fact, very high doses of a muscarinic agonist can produce lethal bradycardia and A-V block. Choline esters have relatively minor direct effects on ventricular function, but they can produce negative inotropy of the atria. 

Prominent effects within the digestive tract include stimulation of salivation and acid secretion, increased intestinal tone and peristaltic activity, and relaxation of most sphincters. Bronchoconstriction and stimulation of secretions are prominent effects in the respiratory system. Muscarinic agonists can also evoke secretion from nasopharyngeal glands. Urination is promoted by stimulation of the detrusor muscle of the bladder and is facilitated by relaxation of the trigone and external sphincter muscles. 

Tacrine has been found to be somewhat effective in patients with mild-to-moderate symptoms of this disease for improvement of cognitive functions. The drug is primarily a reversible cholinesterase inhibitor that increases the concentration of functional ACh in the brain. However, the pharmacology of tacrine is complex the drug also acts as a muscarinic receptor modulator in that it has partial agonistic activity, as well as weak antagonistic activity on muscarinic receptors in the CNS. In addition, tacrine appears to enhance the release of ACh from cholinergic nerves, and it may alter the concentrations of other neurotransmitters such as dopamine and NE. 

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