Cholinergic nicotinic receptor inhibitor

Altinicline (10), being structurally similar to nicotine, is an inhibitor of cholinergic nicotinic receptors for the treatment of Alzheimer s disease. It was synthesized via the Sonogishira coupling of iodochloro analogue 103 with terminal alkyne 104, followed by reduction of the chloride of 105 and removal of the silyl protection group. ... 

These compounds inhibit the hydrolysis of the neurotransmitter acetylcholine by the enzyme acetylcholinesterase within the mammalian nervous system (Zwiener and Ginsburg, 1988). This inhibition causes acetylcholine levels to rise, thus causing cholinergic hyperstimulation at muscarinic and nicotinic receptors. There are important differences in the way carbamates and OPs bind to acetylcholinesterase as well as their abililty to affect the CNS. Carbamates are reversible inhibitors of cholinesterase enzymes. Carbamates create a reversible bond to the cholinesterase enzyme through carbamylation which can spontaneously hydrolyze, reversing toxicity. Carbamate poisoning produces toxicity similar to that of OPs however, the toxicity is usually of a shorter duration and less severe in nature (Lifshitz et al, 1994). In contrast, OPs inhibit cholinesterase via an irreversible bond of phosphate radicals... 

Acetylcholine Approximately 5% of brain neurons have receptors for ACh. Most CNS responses to ACh are mediated by a large family of G protein-coupled muscarinic M receptors that lead to slow excitation when activated. The ionic mechanism of slow excitation involves a decrease in membrane permeability to potassium. Of the nicotinic receptors present in the CNS (they are less common than muscarinic receptors), those on the Renshaw cells activated by motor axon collaterals in the spinal cord are the best-characterized. Drugs affecting the activity of cholinergic systems in the brain include the acetylcholinesterase inhibitors used in Alzheimer s disease (eg, tacrine) and the muscarinic blocking agents used in parkinsonism (eg, benztropine). 

Acetylcholinesterase inhibitors Alzheimer s disease caffeine cholinergic dopaminergic monoamine oxidase muscarinic receptor nicotinic receptor Parkinson s disease Vinca... 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

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