CHOLINERGIC DRUGS AND RELATED AGENTS

CHOLINERGIC DRUGS AND RELATED AGENTS
The autonomic nervous system (ANS) is composed of two divisions sympathetic and parasympathetic. Acetyl choline serves as a neuro transmitter at both sympathetic and parasympathetic pre ganglionic nerve endings.
Cholinergic agents are drugs that either directly or indirectly produce effect similar to acetyl choline (Ach). The neurotransmitter of pre ganglionic neuron is acetyl choline and post ganglionic neuron is nor adrenaline in sympathetic system. Acetyl choline is the neuro transmitter of all pre and post ganglionic neurons of parasympathetic system.
Cholinergic receptors
There are two types of cholinergic receptors on the basis of their ability to be bound by the naturally occurring alkaloids nicotine and muscarine are called nicotinic receptors and muscarinic receptor.
1. Nicotinic receptors
Nicotinic receptors are coupled directly to ion channels and mediate very rapid responses when activated by acetyl choline. These receptors are selectively activated by nicotine and blocked by tubocurarine or hexamethonium. These belongs to ligand -gate ion channel receptors and acetyl choline serve as a gate keeper by interacting with the receptor to modulate passage of ions, principally K + and Na + through the channel. Their activation causes opening of the channel and rapid flow of cation resulting depolarization and generation of action potential.
Sub types : - There are two types
N1 nicotinic receptors - These are present in neuromuscular junction. They are blocked by succinyl choline, d – tubocurarine and decamethonium and stimulated by phenyl trimethyl ammonium.
N2 nicotinic receptors - These are found in autonomic ganglia. They are blocked by hexamethonium and trimethaphan but stimulated by tetra methyl ammonium and diethyl 4-phenyl piperazinium (DMPP).
2.Muscarinic receptors :
Muscarinic receptors play as essential role in regulating the functions of organs in ANS to maintain homeostasis of the organism. The action of acetyl choline on Muscarinic receptor can result in stimulation or inhibition of the organ system affected. Acetyl choline stimulates secretions from salivary and sweat glands, secretions contraction of the gut and constriction of the airways of the respiratory tract.
Sub types: - There are five types of receptors M1, M2, M3, M4 and M5.
1. M1 receptors : They are located in CNS, exocrine glands and autonomic ganglia. These are identified in sub mucosal glands and some smooth muscles. When stimulated M1 receptors cause gastric secretion.
2. M2 receptors : These are called cardiac muscarinic receptors because they are located in atria and conducting tissue of the heart. Their stimulation causes a decrease in the strength and rate of cardiac muscle contraction. M2 receptor activate K+ channels to cause hyper polarization of cardiac cells, resulting in bradycardia.
3. M3 receptors : These are referred to as “glandular” Muscarinic receptor, are located in exocrine glands and smooth muscles. Glandular secretions from lacrimal, salivary, bronchial, pancreatic and mucosal cells in GI tract are characteristics of M3 receptor stimulations.
4. M4 receptors : They are present in tracheal smooth muscle, when stimulated inhibit the release of acetyl choline.
Bio chemical effects of Muscarinic receptor stimulation :
Transmission of synapse involving second messenger is much slower compared with at synapses where ion channels are activated directly. The sequence of bio chemical events in this second messenger system begins with activation of the receptors by an agonist and involves the activation of G – proteins that are bound to a portion of the intracellular domain of the Muscarinic receptors.
G – Proteins consists of 3 sub units, α, β and γ. When the receptor is occupied, the sub unit which has enzymatic activity, catalyses the conversion of GTP to GDP (guanosine diphosphate) which can associate with various enzymes and ion channels. A single drug – receptor complex can active several G – protein molecules and each can remain associated with a target molecule.
Adenylate cyclase is a membrane enzyme is another target of Muscarinic receptor activation. The second messenger cAMP is synthesized with in the cell from adenosine tri phosphate (ATP) by the actions of Adenylate cyclase. The cAMP activate protein kinase which catalyze the phosphorylation of enzymes and ion channels, alter the amount of calcium entering the cell and thus affecting muscle contraction.
But muscarinic receptor activation causes lower levels of cAMP, reducing CAMP protein dependent kinase activating and relaxation of muscle contraction.
Stereo chemistry of acetyl choline :
Acetyl choline exist in number of confirmations. Confirmational isomers of acetyl choline derived from rotation around – O –C – C –N – axis. Four of these confirmations are illustrated by Newman projection below.

CHOLINOMIMETIC (OR) PARASYMPATHOMIMETIC DRUGS
These are agents that mimic the action at Parasympathetic system.
CLASSIFICATION
1.Directly acting Cholinergic drugs (Agonist)
A) Choline Esters – Acetyl choline, Carbochol, Bethanechol, Methacholine.
B) Alkaloids - Pilocarpine
2.Indirectly acting Cholinergic drugs (Anti choline esterase)
A) Reversible Inhibitors – Physostigmine, Neostigmine, Pyridostigmine, Endrophonium chloride, Ambinonium chloride.
B) Irreversible Inhibitors – Pralidoxime chloride, Isoflurphate, Echothiophate iodide, Parathion, Malathion.
Carbochol
Carbochol - Synthesis

SAR for Cholinergic drugs SAR depends upon thr modifications of the following groups
I. Quaternary ammonium group :

1. The onium group is essential for intrinsic activity and contributes to the affinity to receptors.
2. Replacement of nitrogen with sulfur, arsenic or selenium produces less active compounds.
3. Primary, secondary or tertiary amines are less active than acetyl choline.
4. Replacement of methyl groups by ethyl or larger alkyl groups produces inactive compounds.
5. Compounds in which two methyl groups on nitrogen were retained and there were replaced by a larger alkyl groups were found to have considerable activity.

II. Modification of ethylene bridge :

1. Shortening or lengthening of the ethylene group that separates the ester group and ammonium group reduces muscarinic activity.
2. An α- substitution decreases nicotinic activity more extent.
3. Replacement of hydrogen atoms of ethylene bridge by alkyl groups are less active except when a single methyl group is placed either at α or β to the quaternary nitrogen atom.
4. The presence of methyl group α to nitrogen increases nicotinic activity ( Acetyl methyl choline) and β to nitrogen increases muscarinic activity (Methacholine)
5. Hydrolysis by acetyl cholinesterase is more affected by β – substitutions than α – carbon.

III. Modification of ester group :

1. The ester group of acetyl choline contributes to the binding of the compound to the muscarinic receptor.
2. When acetyl group is substituted by its higher homologues produce less active compounds.
3. When the acetyl group is replaced by a carbonyl (carbachol) has both muscarinic and nicotinic property.
4. Esters of aromatic or higher molecular weight acids possess cholinergic antagonist activity.
5. The methyl ester is rapidly hydrolyzed by cholinesterase.
6. When the terminal methyl group is replaced by – NH2 group, the resulting compound is potent cholinergic agent with both muscarinic and nicotinic activities.