PHAR 402

PHAR 402, Dr. Lu

SITES OF DRUGS ACTING AT THE ADRENERGIC SYNAPSES

Reading Assignment:

Foye, W.O. (1995) Principles of Medicinal Chemistry, Chapter 18. Williams & Wilkins , Philadelphia, pp 345-365.

Other References:

1. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9^th ed., McGraw Hill, 1996, New York, pp 118-134.

2. Hieble, J.P., Bondinell, W.E., Ruffolo, R.R., Jr. (1995) "a- and b-Adrenoceptors: From the gene to the clinics. 1. Molecular biology and adrenoceptor subclassification", J. Med. Chem., 36, 3415-3444.

3. Casy, A.F. and Dewar, G.H. (1993) The Steric Factor in Medicinal Chemistry - Dissymmetric Probes of Pharmacological Receptors, Chapters 4 and 5. Plenum Press, New York.

Educational Objectives and Study Guidelines

A student should be able to:

1. Identify the sites at the adrenergic synapses which can be regulated by drugs and explain how a given drug molecule may act to modify the adrenergic responses.

2. Know the chemical structure of R (-) norepinephrine and explain how it bind to the adrenergic receptor.

3. Explain the possible contributions made by each functional group of a drug molecule to its binding to the active site of the adrenergic receptors or to an enzyme which responsible for the biosynthesis or degradation of norepinephrine.

4. Relate the structural features of a compound to their adrenergic receptors selectivity.

5. Relate the structural features of a compound to physicochemical properties, which may have a major effect on its biological response.

6. Predict the biochemical mechanism of action of a biological active compound from its chemical structure.

7. Discuss the structure activity relationships of the subclasses of adrenergic agonists.

PHAR 402, Dr. Lu

Handout # 1 Sites of Drug Action at the Adrenergic Synapses

Site 1: Biosynthesis of norepinephrine (NE) (see handout #3 for detail description), a. Tyrosine hydroxylase reaction is blocked competitively by a-methyltyrosine; b. L-Aromatic amino acid decarboxylase reaction is blocked by a -methyldopa; c. Dopamine-ß-hydroxylase reaction is blocked by dithiocarbamate derivative such as disulfiram (antabuse) and fusaric acid.

Site 2: Storage. Reserpine and tetrabenazine interfere with the uptake-storage mechanism of NE and other biogenic amines. The antipsychotic activities of these compounds will be covered in PHAR 403.

Site 3: Release. Amphetamine appears to cause an increase in the net release of NE. The adrenergic activity of amphetamine analogues will be discussed under adrenergic agonists and the analeptic activities of these compounds will be covered in PHAR 403.

Site 4: postsynaptic receptor interaction. Clonidine appears to be a very potent a -adrenergic agonist. Phenoxybenzamine and phentolamine are effective a-receptor antagonists. The chemical and pharmacological aspects of the adrenergic antagonists will be covered in PHAR 405.

Site 5: Re-uptake. The adrenergic action of NE is terminated primarily by re-uptake of the NE into the presynaptic terminal for re-storage. Drugs acting via this mechanism are used as antidepressants (e.g., desipramine). These compounds will be covered in PHAR 403.

Site 6: Monamine Oxidase (MAO). NE or dopamine (DA) present in a free state within the presynaptic terminal can be degraded by the mitochondria enzymes, MAO (both types A & B). Pargyline is an effective inhibitor of MAO. MAO-A and MAO-B inhibitors are antiparkinsonism drugs or antidepressants (to be covered in PHAR 403).

Site 7: Catechol-O-methyl transferase (COMT). NE can be inactivated by the enzyme COMT, which is believed to be localized outside the presynaptic neuron. Tolcapone is an inhibitor of COMT.

PHAR 402, Dr. Lu

Handout # 2 Discovery of Catecholamines as Neurotransmitters

Figure 18-5. Proposed arrangement for the transmembrane helices of the b₂-adrenergic receptor depicting the binding site for epinephrine as viewed from the extracellular side

· Amino acid sequence of the human b₂ receptor showing the seven transmembrane domain, I-VII, the connecting intracellular and extracellular loops, extracellular glycosylation sites at asparagines 6 and 15, and intrachain disulfide bonds between cysteines 106-184 and 190-191.

· Also indicated are the amino acids identified as participating in neurotransmitter binding -- aspartate 113 in transmembrane domain III, which binds the positively charged amine of the neurotransmitter, and serines 204 and 207 of transmembrane domain V, which form H-bonds with the catechol hydroxyls. Phenylalanine 290 may also participate in agonist binding. Amino acids 222-229 and 258-270 of the third intracellular loop are critical for G-protein coupling, and palmitoylated cysteine 341 is critical for proper adenylyl cyclase activation.