Adrenergic drugs

it contain all new discovered the adrenergic drugs with mechanism of action, structure and synthesis.

1. ADRENERGIC DRUGS DEPARTMENT OF PHARMACEUTICAL CHEMISTRY ISF College of Pharmacy, Moga Presented by- Shalini jaswal M.Pharm 1 st sem Presented to : Dr. Vikram Deep Monga

2. What are adrenergic drugs? Adrenergic drugs are medications that stimulate certain nerves in your body. They do this either by mimicking the action of the chemical messengers epinephrine and nor epinephrine or by stimulating their release. These drugs are used in many life-threatening conditions, including cardiac arrest, shock, asthma attack, or allergic reaction. Catecholamines The neurotransmitters of adrenergic system noradrenaline(norepinephrine) and adrenaline(epinephrine) belongs to a class of substance known as catecholamines. They called catecholamines because they have an alkylamine chain linked to catechol ring. Types of adrenergic receptors There are 2 types of receptor – Alpha receptor Beta receptor

3. Biosynthesis of catecholamines The biosynthesis of NE and adrenaline starts from the amino acid l-tyrosine. Adrenergic Neurotransmitters Biosynthesis of noradrenaline and adrenaline

4. The adrenergic binding site The adrenergic receptors are G-protine couple receptors . The knowledge of binding site is based on the mutagensis studies and molecular modelling. From these studies it has been proposed that the three of the trans membrane helices (TM3, TM5, TM6) are involved in the binding site, These studies also indicate the importance of an aspartic acid residue (Asp-113), a phenylalanine residue(phe-290) and two serine residue(ser-207, ser-204). Modelling studies indicates that these groups can bind to adrenaline or noradrenaline

5. Adrenergic binding sites

6. Classifications of adrenergics receptor agonist

7. Classification of direct acting alpha adrenergic agonist MOA: Adrenergic alpha-agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α₁ and α₂. Alpha 2 receptors are associated with sympatholytic properties. α Adrenergic agonists have the opposite function of alpha blockers Selective agonist alpha-1 adrenergic receptor agonist Phenylephrine Methoxamine Midodrine Metaraminol alpha-2 adrenergic receptor agonist Clonidine Xylazine Guanfacine Guanabenz Apraclonidine Lofexidine

8. methoxamine Metaraminol Clonidine Xylazine Guanfacin guanabenz Apraclonidine Phenylepherine Lofexidine Midodrine alpha-1 adrenergic receptor agonist alpha-2 adrenergic receptor agonist NEWER DRUG

9. synthesis of lofexidine

10. Classification of direct acting beta adrenergic agonist MOA: β adrenergic receptors are coupled to a stimulatory G protein of  adenylyl cyclase . This enzyme produces the second messenger cyclic adenosine monophosphate  ( cAMP ). In the lung, cAMP decreases calcium concentrations within cells and activates protein kinase A. Both of these changes, inactivate myosin light-chain kinase  and activate myosin light-chain phosphatase . In addition, β 2   agonists open large conductance calcium-activated potassium channels and thereby tend to hyperpolarize airway smooth muscle cells. The combination of decreased intracellular calcium, increased membrane potassium conductance, and decreased myosin light chain kinase activity leads to smooth muscle relaxation and bronchodilation .

11. Beta-1 receptor agonist Dobutamine Denopamine Xamoterol Prenalterol Dobutamine Denopamine Xamoterol prenalterol

12. Clenbuterol Isoetarine Salbutamol Terbutaline Colterol Orciprinaline Beta-2 receptor agonist Terbutaline Salbutamol Salmetrol Isoetarine Clenbuterol Orciprinaline Colterol metaproterenol NEWER DRUGS

13. synthesis of clenbuterol synthesis of Orciprinaline

14. Non selective adrenergic agonist MOA: They can stimulate either of the receptor i.e alpha as well as beta or both. Drugs Available Adrenaline Norepinephrine Isoprenaline Dopamine Adrenaline Norepinephrine Isoprenaline Dopamine

15. Mixed acting agonist   Mixed - acting  adrenergic  agonists  are compounds that cause activation of adrenergic receptors by both direct binding as well as release of endogenously-stored norepinephrine from presynaptic terminal. Ephedrine pseudoephedrine Ephedrine Pseudoephedrine

16. Indirect acting adrenergic agonist Indirect-acting adrenergic agonists are compounds that cause activation of adrenergic receptors by mechanisms other than their direct binding . MOA for indirect acting Indirectly acting adrenergic agonists affect the uptake and storage mechanisms involved in adrenergic signalling . Two uptake mechanisms exist for terminating the action of adrenergic catecholamines - uptake 1 and uptake 2 . Uptake 1 occurs at the presynaptic nerve terminal to remove the neurotransmitter from the synapse. Uptake 2 occurs at postsynaptic and peripheral cells to prevent the neurotransmitter from diffusing laterally. There is also enzymatic degradation of the catecholamines by two main enzymes -  monoamine oxidase  and  catechol -o-methyl transferase . Respectively, these enzymes oxidise monoamines (including catecholamines ) and methylate the hydroxal groups of the phenyl moiety of catecholamines . These enzymes can be targeted pharmacologically. Inhibitors of these enzymes act as indirect agonists of adrenergic receptors as they prolong the action of catecholamines at the receptors.

17. cocain Selegiline entacapone amphetamine tyramine The indirect acting adrenergic drugs may be classified as. Releasing agents- amphetamines, Uptake inhibitors- cocain MAO inhibitors- selegiline COMT inhibitors- entacapone

18. SAR of alpha and beta receptor agonist

19. Separation of Aromatic Ring and Amino Group the greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group Substitution on the Amino Nitrogen Determines - or -Receptor Selectivity

20. R2, Substitution on the -Carbon (Carbon-2). Methyl or ethyl substitution on the a-carbon of the ethylamine side chain reduces direct agonist activity at both α - and β -receptors . a-Substitution also significantly affects receptor selectivity. a-methylnorepinephrine , it is the erythro (1R,2S) isomer that possesses significant activity at α 2-receptors . Substitution on either carbon-1 or carbon-2 yields optical isomers. (1R,2S) isomers seem correct configuration for direct-acting activity. The more potent enantiomer has the (1R) configuration. This enantiomer is typically several 100-fold more potent than the enantiomer with the (1S) configuration

21. Substitution on the Aromatic Ring because the resorcinol ring is not a substrate for COMT , B-agonists that contain this ring structure tend to have better absorption characteristics and a longer DOA than their catechol-containing counterparts. replacement of the meta-OH of the catechol structure with a hydroxymethyl group gives agents are selective beta-2 agonist. Modification of the catechol ring can also bring about selectivity at α - receptors as it appears that the catechol moiety is more important for α 2- activity than for α 1-activity .

22. Adrenergic antagonist An  adrenergic antagonist  is a drug that inhibits the function of adrenergic receptors .

23. Properties of all generations

24. General pharmacology of adrenergic antagonist

25. Alpha receptor antagonist MOA: Alpha-blockers, also known as α-blockers or α- adrenoreceptor antagonists, are a class of pharmacological agents that act as antagonists on α-adrenergic receptors.  Alpha-1 selective quinalzoline derivatives Prazosin Terazosin Doxazosin Silodosin Alfuzosin Tamsulosin Prazosin Terazosin Doxazosin Alfuzosin Tamsulosin Silodosin NEWER DRUGS

26. synthesis of Alfuzosin

27. Indole derivative Indoramine Indoramine Alpha-2 selective Yohimbine Atipamezole Efaroxan Idazoxan Rauwolscine yohimbine Rauwolscine Idazoxan Atipamezole Efaroxan NEWER DRUGS

28. Non-selective Haloalkylamine derivatives Phenoxybenzamine Phentolamine Imidazoline derivative Tolazoline Ergot alkaloids ergotamine Phenoxybenzamine Phentolamine Urapidil Ergotamine

29. Classification of Beta receptor antagonist MOA:- Beta blockers inhibit these normal epinephrine- and norepinephrine -mediated sympathetic actions β 1 - selective agents :- Selectively act on beta 1 receptor and antagonise the action. Sotalol Timolol Acebutolol Atenolol Betaxolol Bisoprolol Celiprolol Metoprolol Sotalol Timolol Acebutolol Atenolol NEWER DRUG

30. Betaxolol Bisoprolol Celiprolol Metoprolol NEWER DRUG

31. Synthesis of Celiprolol

32. Beta receptor antagonist β 2 - selective agent: Selectively act on beta-2 receptor and antagonise the action. Butaxamine ICI-118,551 Butaxamine ICI-118,551 NEWER DRUGS

33. Synthesis of Butaxamine

34. Non Selective: antagonise action of both beta 1 and beta-2 generally used as beta 2 blockers Propanolol Bucindolol Carteolol Carvedilol Labetalol Nadolol Oxprenolol Penbutolol Pindolol Beta receptor antagonist Propranolol Bucindolol Carteolol Carvedilol

35. Penbutolol Oxprenolol Nadolol Labetalol Pindolol NEWER DRUGS

36. Synthesis of Penbutolol Synthesis of Oxeprenolol

37. SAR of Beta receptor antagonist i.e R isomer is active