Adrenergic Pharmacology Tutorial using CHIME

Adrenergic Stucture-Function relationships

Neurotransmitters and hormones act by binding to specific protein targets, usually cell surface receptors. They bind to a specific site on these proteins, through a "lock and key" style interaction, i.e. the shape of the molecule fits a complementary pocket in the receptor. This is only an approximation, as both the neurotransmitter molecules themselves and the protein are somewhat flexible, and electrostatic and polar interactions are important as well, but provides a useful mental image for imagining ligand (neurotransmitter/drug) receptor interaction.

Neurotransmitters and hormones act by producing changes in the conformation of the receptor they bind to, this conformational change leads to activation of signal transduction pathways either directly or, in the case of the adrenoceptors, indirectly (via G-proteins). In the case of adrenoceptors, these proteins have seven transmembrane domain spanning helicies (numbered I-VII), which aggregate together into a rough cylinder with a pore in the centre. Noradrenaline and adrenaline bind on the inside of this pore. [Go to 3D model]

This panel shows the b2-adrenoceptor in cartoon mode, with interconnecting strands omitted for clarity. This 3D structure is a model based on the rhodopsin receptor to guide folding of the b2-adrenoceptor sequence. The view is from above the molecule looking down into the pore. Use the buttons to highlight various parts of the molecule that are important for function. Click the button again to clear your selection.

Adrenaline, fits into the pore between loops III, V and VI.

Residues important for binding and function. Shown are
Serines 204 and 207, which bind the catechol group,
Phenylalanine 290 which forms a pi bond with the catechol ring,
Asparagine 293 which binds the hydroxyl group on the b carbon
Aspartate 113 which binds the terminal nitrogen.

Zoom into the binding site for more details.

In the case of the b2-adrenoceptor shown above, for both adrenaline and noradrenaline the terminal nitrogen binds to the apartate residue at position 113 on loop III, the hydroxyl group on the b-carbon binds to asparagine 293 on loop VI, and the hydroxyls on the benzene ring bind to serines 204 and 207 on loop V. Similar arrangements occur for the other adrenoceptors.

The following table allows you to further explore the structure of catecholamines as they relate to adrenoceptor activity. [Go to structural model]

GREY= carbon, RED = oxygen, BLUE= Nitrogen, WHITE = hydrogen.
This panel shows the catecholamine noradrenaline in planar ball and stick mode, use the buttons to highlight various parts of the molecule that are important for function. Click the button again to clear your selection.

Catechol group, bulky substitutions here prevent interaction with binding sites on loop V of adrenoceptors, resulting in weak agonists (eg pindolol) or antagonists (eg. propranolol) .

Alpha Carbon, substitutions here block oxidation by Monoamine Oxidases.

Beta Carbon an OH or similar group is needed here for agonist activity (interacts with Asp in LoopVI of adrenoceptors).

R1 This OH group plays a critical role in interaction with adrenoceptor Loop V and agonist activity. Phenylepherine, which lacks an OH at this position, is much less potent than adrenaline.

R2 This OH group plays an important role in interaction with Loop V and agonist activity. However, removal of R1 and R2 also improves absorption and biodistribution.

R3 The terminal nitrogen is important in determining b-adrenoceptor selectivity. Substitution of methyl (adrenaline) or isopropyl (isoprenaline) groups improves selectivity for b-adrenoceptor and lowers activity at a-adrenoceptors (e.g. isoprenaline is very weak at a-adrenoceptors).

Drugs act by mimicking the structure of the natural neurotransmitter and hormones. There may be an almost direct structural correspondence between the drug and hormone (e.g. phenylepherine and adrenaline) or the structures may be superficially quite different (e.g. clonidine and adrenaline), but the drugs shape and electrostatic charge distribution mimics the shape and charge of the natural compound. Whether a drug is an agonist or antagonist depends on a number of structural issues. Replacing the catechol ring with a bulky substituent (e.g. propranolol) makes it likely that the resulting compound will block adrenoceptors, as the interactions on loop V are important to agonist activity. The diagram below shows a schematic view of the binding of adrenaline and the antagonist alprenolol to the b2-adrenoceptor, showing how the similarities and differences in their binding.
adrenaline alprenolol
Comparison of binding of Adrenaline (left hand panel) and the antagonist alprenolol (Right hand panel) to the b2-adrenoceptor. The majority of the loops have been omitted for clarity.

The following table allows you to explore these features in more detail. [Go to 3D overlays]

Toggle Spin

Adrenaline, endogenous adrenergic agonist

Propranolol, b-adrenergic competitive antagonist
Adrenaline and Propranolol side by side
Overlay Adrenaline and Propranolol Select Propranolol

Pindolol, functional b-antagonist with intrinsic activity
Adrenaline and Pindolol side by side
Overlay Adrenaline and Pindolol

Phenylepherine, a-adrenergic agonist
Adrenaline and Phenylepherine side by side
Overlay Adrenaline and Phenylepherine

Clonidine, a2-adrenergic agonist with imidazoline structure
Adrenaline and Clonidine side by side
Overlay Adrenaline and Phenylepherine

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Structures are either from the Structure Data Base of the Department of Structural Organic Chemistry, Tokyo University of Pharmacy and Life Science or drawn by Dr. Musgrave. Visualisation is through the MDL CHIME plug-in. This page produced by Dr. Ian Musgrave of the Department of Clinical and Experimental Pharmacology, University of Adelaide.