PPTS OF SAR OF CHETACHOLAMINES, CAPHELOSPORINES AND CORTICOSTEROIDS

1. SAR OF CATECHOLAMINES, CEPHALOSPORINS AND CORTICOSTEROIDS Presented by Dr. nutanbalagoswami, Associate professor, Pharmacology dept., Govt. medical college, Bhavnagar.

2. Structure-activity relationships (SAR)

3. Structure-activity relationships (SAR) • Structure-activity relationships (SAR) are the traditional practices of medicinal chemistry which try to modify the effect or the biological activity of chemical compounds by modifying their chemical structure. • Medicinal chemists use the techniques of chemical synthesis to insert new chemical groups into the biomedical compound and test the modifications for their biological effects.

4. Structure-activity relationships (SAR) • This enables the identification and determination of the chemical groups responsible for evoking a target biological effect in the organism. • This method was later refined to build mathematical relationships between a chemical structure and its biological activity, known as quantitative structure-activity relationships (QSAR).

5. Structure-activity relationships (SAR) • Changing the chemical structure of a compound slightly, results in change in biological activity of compounds. Effect of different functional groups on biological activity of compounds are as follows: • Effect of Alkyl group • Effect of Hydroxyl group • Effect of Acidic group • Effect of Amino group • Effect of Carboxyl group • Effect of Nitro group • Effect of Isomerism

6. Structure-activity relationships (SAR) 1. EFFECT OF ALKYL GROUP

7. 1. EFFECT OF ALKYL GROUP • Effect on Benzene Ring Benzene Toulene • Methyl group increases the activity of compound • But if more alkyl group is added, activity of compound decreases.

8. Effect on Catechol Ring O-Catechol M-Resorcino P-Hydroquinone (Toxic) (Less toxic) (Very less toxic) • Catechol, resorcinol & hydroquinone have different toxicities due to difference in position of –OH group. • If –OH group of these catechol replaced with –OCH3 group then compound become very less toxic.

9. Structure-activity relationships (SAR) 2. EFFECT OF HYDROXYL GROUP

10. 2. EFFECT OF HYDROXYL GROUP • Addition of –OH group in aliphatic ring decreases the toxicity and activity. CH2OHCOOH CH2OH COOH GlycolOxalicacid • Addition of –OH group in aromatic ring increases the toxicity and biological activity.

11. AROMATIC RING BenzenePhenol (Less Toxic) (More Toxic) Benzoic Acid Salicyclic Acid (Non-toxic) (Toxic) • Benzoic acid is antiseptic but when –OH group is added it becomes Salicyclic acid which is used as analgesic. • So Addition of –OH group increases biological activity.

12. Structure-activity relationships (SAR) 4. EFFECT OF AMINO GROUP

13. 4.EFFECT OF AMINO GROUP • Addition of amino group to aromatic compound results in increase in toxicity of compound. Benzene Aniline (less toxic) (Toxic) Phenol Aminophenol

14. Structure-activity relationships (SAR) 5. EFFECT OF CARBOXYL GROUP

15. 5. EFFECT OF CARBOXYL GROUP • Addition of –COOH group in a molecule of poisonous drug lowers the biological activity & toxicity. • Effect on Benzene ring Benzene Benzoic acid (toxic) (less toxic) • Effect on Phenol Phenol Phenolic acid (antiseptic) (Analgesic)

16. Structure-activity relationships (SAR) 7. EFFECT OF ISOMERISM

17. 7. EFFECT OF ISOMERISM • EFFECT OF POSITION ISOMERISM Cocaine is a local anesthetic but if the position of –COOCH3 group is changes we get α-cocaine which is inactive having no anesthetic activity. Cocaine

18. EFFECT OF OPTICAL ISOMERISM Enantiomers (optical isomers) can have large differences in potency, receptor fit, biological activity, transport and metabolism. For example, levo-phenol has narcotic, analgesic, and antitussive properties, whereas its mirror image, dextro-phenol, has only antitussive activity. Levo form of Atropine is more active than its dextro form.

19. EFFECT OF GEOMETRIC ISOMERISM • Occur as a result of restricted rotation about a chemical bond, owing to double bonds or rigid ring system in the molecule. • They are not mirror images and have different physicochemical properties and pharmacological activity. Because different distances separate the functional groups of these isomers. • For example, cis-diethylstilbestrol has only 7% of the oestrogenic activity of trans- diethylstilbestrol

20. Direct-Acting Sympathomimetics

21. Direct-Acting Sympathomimetics

22. Direct-Acting Sympathomimetics • The parent structure of many adrenergic drugs is β-phenylethylamine. • The modifications of β-phenylethylamine influence not only the mechanism of action, the receptor selectivity, but also their absorption, oral activity, metabolism, and thus duration of action (DOA).

23. Direct-Acting Sympathomimetics • For the direct-acting sympathomimetic amines, maximal activity is seen in β-phenylethylamine derivatives containing (a) a catechol and (b) a (1R)-OH group on the ethylamine portion of the molecule. • Such structural features are seen in the prototypical direct-acting compounds NE, E, and ISO.

24. Optical Isomerism For CAs, the more potent enantiomer has the (1R) configuration.

25. Separation of Aromatic Ring and Amino Group The greatest adrenergic activity occurs when two carbon atoms separate the aromatic ring from the amino group.

26. R1, Substitution on the Amino Nitrogen Determines α- or β-ReceptorSelectivity • Primary and secondary amines have good adrenergic activity, whereas tertiary amines and quaternary ammonium salts do not. • The nature of the amino substituent also affects the receptor selectivity of the compound. • As the size of the nitrogen substituent increases, α-receptor agonist activity generally decreases and β-receptor agonist activity increases.

27. R1, Substitution on the Amino Nitrogen Determines α- or β-Receptor Selectivity • Thus, NE has more α-activity than β-activity and E is a potent agonist at α-, β1-, and β2-receptors. • N-tert-butyl group enhances β2-selectivity.

28. R2, Substitution on the α-Carbon (Carbon-2). • Substitution by small alkyl group (e.g., CH3- or C2H5-) slows metabolism by MAO. • This is very important for non-catechol compounds where the addition of small alkyl group increases the resistance to metabolism and lipophilicity. • so such compounds often exhibit enhanced oral effectiveness and greater CNS activity than other compounds that do not contain an α-alkyl group.

29. OH substitution on the β-carbon (carbon-1) • 1- Greatly enhances agonist activity at both α- and β-receptors. • 2- Largely decreases CNS activity because it lowers lipid solubility.

30. Substitution on the Aromatic Ring • Maximal α- and β-activity also depends on the presence of 3´ and 4´ OH groups. • Compounds without one or both phenolic OH substituents are not metabolized by COMT, and they are orally active and have longer duration of action. • Although the catechol moiety is important maximal agonist activity at adrenoceptors, it can be replaced with other substituted phenyl moieties to provide selective adrenergic agonists.

31. CAs without OH Groups • The loss of OH groups on the ring and the β-OH group on the side chain lead to compounds that: • 1- Act almost by causing the release of NE from sympathetic nerve terminals (loss of direct sympathomimetic activity). • 2- - Have more central activity (more lipophilic compounds).

32. Imidazolines and α-Adrenergic Agonists • A second chemical class of α-agonists is the imidazolines. • These imidazolines can be nonselective, or they can be selective for either α1- or α2-receptors.

33. Imidazolines and α-Adrenergic Agonists • Structurally, most imidazolines have their heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type of bridging unit. • The optimum bridging unit (X) is usually a single methylene group or amino group.

34. ENDOGENOUS CATECHOLAMINES The three naturally occurring catecholamines DA, NE, and E are used as therapeutic agents.

35. ENDOGENOUS CATECHOLAMINES α-ADRENERGIC RECEPTOR AGONISTS

36. α-ADRENERGIC RECEPTOR AGONISTS • All selective α1-agonists have therapeutic activity as vasoconstrictors. • Structurally, they include (a) phmetaraminol, and methoxamine and (b) 2-arylimidazolines such as enylethanolamines such as phenylephrine, xylometazoline, oxymetazoline, tetrahydrozoline, and naphazoline.

37. Phenylephrine • It differs from E only in lacking a p-OH group. • It is orally active, and its duration of action (DOA) is about twice that of E because it lacks the catechol moiety and thus is not metabolized by COMT.

38. Phenylephrine • It is used for hypotension and as a nasal decongestant in both oral and topical preparations.

39. Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline • They are 2-aralkylimidazolines α1-agonists. • These a vasoconstrictive effects as nasal and ophthalmic decongestants.

40. Naphazoline, tetrahydrozoline, xylometazoline, and oxymetazoline • They have agents are used for their limited access to the CNS, because they essentially exist in an ionized form at physiological pH caused by the very basic nature of the imidazoline ring.

41. Clonidine • It differs from 2-arylimidazoline α1-agonists mainly by the presence of chlorine groups and a NH bridge. • Clonidine has antihypertensive activity due to its ability to interact with α2-receptor in the brain which cause a decrease in sympathetic out flow CNS.

42. Clonidine • For clonidine, the(typically pKa = 13.6) is decreased to 8.0 because of the inductive and basicity of the guanidine group resonance effects of the dichlorophenyl ring. • Thus, at physiological pH, clonidine will exist to a significant extent in the nonionized form required for passage into the CNS.

43. Methyldopa (L-α-methyldopa) • It differs structurally from L-DOPA only in the presence of a α-methyl group. • Methyldopa is transported actively into CNS, where it is decarboxylated by AADC in the brain to (1R, 2S)-α-methyldopamine. • This intermediate, in turn, is stereospecifically β-hydroxylated by DBH to give the (1R, 2S)- α -methylnorepinephrine.

44. Methyldopa (L-α-methyldopa) • This active metabolite is a selective α2-agonist. • It is currently postulated that α -methylnorepinephrine acts on α2- receptors in the CNS in the same manner as clonidine, to decrease sympathetic outflow and lower blood pressure.

45. DUAL α- AND β-AGONISTS/ANTAGONISTSDobutamine • It possesses a center of asymmetry, and used clinically as racemic mixture. • The (-) isomer of dobutamine is a potent α1-agonist. • In contrast, (+)- dobutamine is a potent α1-antagonist, which can block the effects of (-)- dobutamine. • Importantly, the effects of these two isomers are mediated via β1-receptors.

46. DUAL α- AND β-AGONISTS/ANTAGONISTSDobutamine • Both isomers appear to be full agonists. • It is a positive inotropic agent administered intravenously for congestive heart failure. • Dobutamine contains a catechol group and is orally inactive and thus is given by intravenous infusion.

47. ENDOGENOUS CATECHOLAMINES β-ADRENERGIC RECEPTOR AGONISTS

48. β-ADRENERGIC RECEPTOR AGONISTS Isoproterenol • Because of an isopropyl substitution on the nitrogen atom, it has virtually no α-activity. • However, it does act on both β1- and β2-receptors. • The cardiac stimulation caused by its β1-activity and its lack of oral activity (why?) have led to its diminished use and favoring the more selective β – agonists.

49. β2-Adrenergic Receptor AgonistsAlbuterol, pirbuterol, salmeterol and Formoterol • They are selective β2 mainly used as bronchodilator. • They are not metabolized by either COMT or MAO. • They are thus exhibit a longer duration of action than isoproterenol. • 3-CH2OH,4-OH & OH on β & no α & at N atom it is replace by C(CH3) 3

50. β3 - Adrenergic Receptor Agonists. • Activation of the β3-receptor is thought to be a possible approach for the treatment of obesity, type 2 diabetes mellitus, and frequent urination. • Therefore, it is an attractive target for drug discovery. Selective β 3 - agonists have been developed, but they have not been approved for therapeutic use.