ADRENERGIC RECEPTORS:INTRODUCTION:-

The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamine, especially nor adrenaline (nor epinephrine) and adrenaline (epinephrine). Although dopamine is a catecholamine, its receptors are in a different category. Many cells possess these receptors, and the binding of an agonist will generally cause a sympathetic response (e.g. the fight-or-flight response). For instance, the heart rate will increase and the pupils will dilate, energy will be mobilized, and blood flow diverted from other nonessential organs to skeletal muscle. BASIC STRUCTURES:PHENYLETHANOLAMINE:-

PHENYLETHYLAMINE:-

ALPHA1, ALPHA2 BETA1, BETA2, BETA3 AGONIST AND ANTAGONIST DERIVATIVES:-

RECEPTORS

AGONIST POTENCY ORDER

SELECTED ACTION OF AGONIST

AGONISTS

ANTAGONISTS.

1: A, B, D

Nor epinephrine epinephrine isoprenaline

Smooth muscle contraction

(Alpha-1 agonists) Noradrenaline Phenylephrine Methoxamine Cirazoline Xylometazoline

(Alpha-1 blockers) (TCA:s) Amitriptyline Clomipramine Doxepin Trimipramine Phentolamine Prazosin Tamsulosin Terazosin

Alpha-2 blockers) 2: A, B, C Epinephrine Smooth muscle norepinephrine relaxation and >> isoprenaline neurotransmitter inhibition (Alpha-2 agonists)

Lofexidine Xylazine Tizanidine Guanfacine Amitraz Clonidine

Phentolamine Yohimbine Idazoxan Atipamezole

Beta blockers) 1 Isoprenaline > Heart muscle epinephrine = contraction norepinephrine

Noradrenaline Isoprenaline Dobutamine

Metoprolol Atenolol

(Short/long) 2 Isoprenaline > Smooth muscle epinephrine >> relaxation norepinephrine

(Beta blockers)

Salbutamol (Albuterol in USA) Bitolterol mesylate Formoterol Isoprenaline Levalbuterol Metaproterenol Salmeterol Terbutaline Ritodrine

Butoxamine Propranolol

Isoprenaline = Enhance lipolysis norepinephrine > epinephrine

Amibegron Solabegron

SR 59230A

STRUCTURES OF ALPHA 1 AGONIST AND ANTAGONIST:-

NOR-ADRENALINE

PHENYLEPHRINE.

METHOXAMINE.

PHENTOLAMINE.

PRAZOSIN.

AMITRIPTYLINE

STRUCTURES OF ALPH 2 AGONIST AND ANTAGONIST.

CLONIDINE

AMITRAZ

ATIPAMEZOLE.

IDAZOXAN

STRUCTURES OF BETA 1 AGONIST AND ANTAGONIST.

DOBUTAMINE

ISOPRENALINE

ATENOLOL.

STRUCTURES OF BETA2 AGONIST AND ANTAGONISTS

SALBUTAMOL

TERBUTALINE

PROPANOLOL

STRUCTURE OF BETA3 AGONIST AND ANTAGONISTS:-

SOLABEGRON

SR- 59230A

STRUCTURE ACTIVITY RELATION OF PHENYLETHYLAMINE DERIVATIVES:The group of phenethylamine derivatives is referred to as the phenethylamine. Substituted phenethylamine, substituted amphetamines, and substituted methylenedioxyphenethylamines (MDxx) are a series of broad and diverse classes of compounds derived from phenethylamine that include stimulants, psychedelics, and entactogens, as well as anorectics, bronchodilators, decongestants, and antidepressants, among others. a phenethylamine core with a methyl group attached to the alpha carbon resulting in amphetamine, along with additional substitutions. Examples of amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone amphetamine and methamphetamine which lack both ring substituents and a side chain hydroxyl, are sufficiently lipophilic to cross the blood brain barrier readily and cause dramatic CNS stimulation. Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH). Ephedrine is a sympathomimetic amine. The principal mechanism of its action relies on its indirect stimulation of the adrenergic receptor system, which is part of the sympathetic nervous system (SNS), by increasing the neither activity of nor adrenaline at the post-synaptic and -receptors. The presence of direct interactions with -receptors is unlikely, but still controversial. Action upon the central nervous system (CNS) is limited because ephedrine only crosses the blood-brain barrier weakly and not very efficiently.

The presence of an N-methyl group decreases binding affinities at -receptors, compared with nor ephedrine. On the other hand ephedrine binds better than N-methyl ephedrine, which has an additional methyl group at the N-atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity
Both ephedrine and pseudoephedrine act as a bronchodilator

AMPHETAMINE

EPHEDRINE

METHAMPHETAMINE

STRUCTURE ACTIVITY RELATION OF PHENYLETHANOLAMINE DERIVATIVES:1. Primary or Secondary Amine, charged at physiological pH 2. Hydroxyl at Beta carbon in the R configuration for maximum effect 3. R1, R2, R3 control selectivity and Metabolism
BASIC STRUCTURE

Disruption of the Catechol inhibits COMT Metabolism Monoamine Oxidase

o

Agonist SAR Substitutions Metabolism

R1 substitutions

Isopropyl slow, but do not block Tertiary Butyl blocks

R2 substitutions

Methyl slow
Ethyl block

R1 - larger than a methyl R1 - Larger than isopropyl generally target Beta-2 Adrenergic Receptors R2 - Methyl or larger R3
o o o

Beta Receptor Selectivity SAR Substitutions

If only one hydroxyl, must be 4' If two hydroxyls, many combination of 3,4,5 are possible Can be as large a formyl, but must be able to hydrogen bond

All have hydroxyl at beta carbon, except Dobutamine which is special

Alpha Receptor Selectivity SAR Substitutions

R1 Guanidine Alpha
o

and Imidazoline

are selective for

Guanidine, for exam purposes, is almost always alpha-2 selective

R1 - Methyl or smaller R2 - S (-) Enantiomer R2 - must be no larger than methyl R3 - Lone hydroxyl at 3' is selective for Alpha-1 Adrenergic Receptors (Phenylephrine) R3 - 2,5 dimethoxy alpha selective

R3 - lipophilic (halide) ortho substitutions promote alpha-2 selectivity.

Oxymetazoline Isoproterenol Bitolterol Colterol Isoetharine Terbutaline Labetalol Sotalol Dobutamine

Drugs Following the Phenyl ethanolamine SAR

REFERENCES:-

http://drtedwilliams.net/kb/index.php?pagename=Phenylethanolamine%20SAR http://en.wikipedia.org/wiki/Ephedrine http://en.wikipedia.org/wiki/Methamphetamine http://www.ei-resource.org/articles/mental-and-emotional-problem-articles/hormonal-treatment-ofdepression-with-phenylethylamine-(pea)/ BOOK:Foyes principles of medicinal chemistry.