Lecture 10 2024 Pharmaceutical Chemistry - University of Alkafeel PDF

University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ CAs without OH Groups: Phenylethylamines that...

University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ CAs without OH Groups: Phenylethylamines that lack OH groups on the ring and the β-OH group on the side chain lack the direct sympathomimetic action and act by causing the release of NE from sympathetic nerve terminals. The resultant compounds are more lipophilic and so cross the BBB more readily and have more central activity. ex, amphetamine and methamphetamine exhibit considerable CNS activity. CAs without one or both phenolic OH substituents are, however, not metabolized by COMT, and so they are not inactivated in the intestinal mucosa and in the liver by this enzyme before reaching the systemic circulation leading to compounds have longer DOA. Imidazolines and α-Adrenergic Agonists: Unlike β-adrenoceptors, α-adrenoceptors exhibit a far more diverse variety of structures that give rise to a second chemical class of α-agonists (and are thus vasoconstrictors) called imidazolines. These imidazolines can be nonselective, or they can be selective for either α1- or α2-receptors. Structurally, most imidazolines have their heterocyclic imidazoline nucleus linked to a substituted aromatic moiety via some type of bridging unit. Agonist activity is enhanced when the aromatic ring is substituted with halogen substituents like chlorine (Cl) or small alkyl groups like methyl group, particularly when they are placed in the two ortho positions. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ α-ADRENERGIC RECEPTOR AGONISTS All selective α1-agonists have therapeutic activity as vasoconstrictors. Structurally, they include (a) Phenylethanolamines such as phenylephrine and metaraminol. Phenylephrine is a prototypical selective direct-acting α1-agonist. It differs from E only in lacking a p-OH group. It is orally active, and its DOA is about twice that of E because it lacks the catechol moiety and thus is not metabolized by COMT. However, its oral bioavailability is less than 10% because of its hydrophilic properties (log P = 0.3). Lacking the p-OH group makes it is less potent than E and NE but it is a selective α1-agonist and thus a potent vasoconstrictor. It is used similarly to metaraminol and methoxamine for hypotension. Another use is in the treatment of severe hypotension resulting from either shock or drug administration. It also has widespread use as a nonprescription nasal decongestant in both oral and topical preparations. In the eye, it is used to dilate the pupil and to treat open-angle glaucoma. In addition, it is used in spinal anesthesia to prolong the anesthesia and to prevent a drop in blood pressure during the procedure. It is relatively nontoxic and produces little CNS stimulation. (b) - 2-aralkylimidazolines such as xylometazoline (Otrivin), oxymetazoline, tetrahydrozoline, and naphazoline. are 2- aralkylimidazolines α1-agonists. These agents are used for their vasoconstrictive effects as nasal and ophthalmic decongestants. - Although nearly all β-agonists are phenylethanolamine derivatives, α-receptors accommodate more diverse chemical structures. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ - All 2-aralkylimidazoline α1-agonists contain a one-carbon bridge between C-2 of the imidazoline ring and a phenyl ring, and thus a phenylethylamine structure feature is there. - Ortho-lipophilic groups on the phenyl ring are important for α- activity. However, meta or para-bulky lipophilic substituents on the phenyl ring may be important for the α1-selectivity. - They have 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 (pKa = 10–11). - Xylometazoline and oxymetazoline have been used as topical nasal decongestants because of their ability to promote constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect. Oxymetazoline also has significant affinity for 2A- receptors. (c) Clonidine differs mainly by the presence of o-chlorine groups and an NH bridge which afford better activity at α2 receptors. Clonidine can exhibit hypotensive effect as a result of the ability of clonidine to enter into the CNS and stimulate α2-receptors leading to a decrease in sympathetic outflow from the CNS, which in turn leads to decreases in peripheral vascular resistance and blood pressure. Clonidine University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ β-ADRENERGIC RECEPTOR AGONISTS 1. Isoproterenol: It is a nonselective and prototypical β-agonist (β2/β1=1). 2. Metaproterenol, terbutaline,and fenoterol: They are belong to the structural class of resorcinol bronchodilators that have 3′,5′-diOH groups of the phenyl ring (rather than 3′,4′-diOH groups as in catechols). 3. Albuterol, pirbuterol, and salmeterol are examples of selective β2- agonists whose selectivity results from replacement of the meta-OH group of the aromatic ring with a hydroxymethyl moiety. They are used as bronchodilators. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ INDIRECT-ACTING SYMPATHOMIMETICS They enter the nerve ending by way of the active-uptake process and displace NE from its storage granules leading to release endogenous NE. Structure-activity relationship: - The indirect-acting drugs that are used therapeutically are not catechol derivatives and, in most cases, do not even contain an OH moiety. - In contrast with the direct-acting agents, the presence of a β-hydroxyl group decreases, and an α-methyl group increases, the effectiveness of indirect- acting agents. - The presence of nitrogen substituents decreases indirect activity, with substituents larger than methyl groups rendering the compound virtually inactive. - Phenylethylamines that contain a tertiary amino group are also ineffective as NE-releasing agents. Examples: amphetamine and p-tyramine. L-(+)-Pseudoephedrine. It is a naturally occurring alkaloid from the Ephedra species. This agent is found in many OTC nasal decongestant and cold medications. Although it is less likely to increase blood pressure than ephedrine, it should be used with caution in hypertensive individuals, and it should not be used in combination with MAO inhibitors. It is the (S,S) diastereoisomer of ephedrine. Whereas ephedrine has a mixed mechanism of action, L-(+)-pseudoephedrine acts mostly by an indirect mechanism and has virtually no direct activity. The structural basis for this difference in mechanism is the stereochemistry of the carbon atom University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ possessing the β-OH group. In pseudoephedrine, this carbon atom possesses the (S) configuration, which must be in (R) configuration for a direct-acting effect at adrenoceptors and this is occurs with ephedrine. SYMPATHOMIMETICS WITH A MIXED MECHANISM OF ACTION Those phenylethylamines considered to have a mixed mechanism of action usually have no hydroxyls on the aromatic ring but do have a β-hydroxyl group. D-(-)-Ephedrine. The pharmacological activity of (1R,2S)-D-(-)-ephedrine resembles that of epinephrine. The drug acts on both α- and β-receptors. Its ability to activate β-receptors probably accounted for its earlier use in asthma. Lacking H-bonding phenolic OH groups makes ephedrine less polar and, thus, crosses the BBB far better than do other CAs. Therefore, ephedrine has been used as a CNS stimulant and exhibits side effects related to its action in the brain. The drug is not metabolized by either MAO or COMT and therefore has more oral activity and longer DOA than E. Ephedrine has two asymmetric carbon atoms; thereby creating four optically active isomers. The erythro racemate is called ephedrine, and the threo racemate is known as pseudoephedrine. Ephedrine and its salts are used locally to constrict the nasal mucosa and cause decongestion and to dilate the pupil or the bronchi. Systemically, it is effective for asthma, hay fever, and urticaria. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ ADRENERGIC RECEPTOR ANTAGONISTS (BLOCKERS) α-Blockers Because α-agonists cause vasoconstriction and raise blood pressure, α-blockers should be therapeutically used as antihypertensive agents. Unlike the β-blockers, which bear clear structural similarities to the adrenergic agonists NE, E, and ISO, the α-blockers consist of several compounds of diverse chemical structure that bear little obvious resemblance to the α-agonists. Prazosin, terazosin, and doxazosin: They are quinazoline derivatives and are α1-blockers. Structurally, these agents consist of three components: the quinazoline ring, the piperazine ring, and the acyl moiety. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ The 4-amino group on the quinazoline ring is very important for α1-receptor affinity. Piperazine moiety attached to the quinazoline ring can be replaced with other heterocyclic moieties (e.g., piperidine moiety) without loss of affinity. The main difference between prazosin, terazosin, and doxazosin lies in their pharmacokinetic properties. These differences are dictated by the nature of the acyl moiety attached to the piperazine ring. These drugs dilate both arterioles and veins and are thus used in the treatment of hypertension. They offer distinct advantages over the other α-blockers, because they produce peripheral vasodilation without an increase in heart rate or cardiac output. This advantage is attributed to the fact that prazosin blocks post junctional α1-receptors selectively without blocking presynaptic α2-receptors. Contraction of the smooth muscle of prostate gland, prostatic urethra, and bladder neck is also mediated by α1-adrenoceptors, with α1A being predominant, and blockade of these receptors relaxes the tissue. For this reason, these agents are also used in the treatment of BPH, where they help improve urination flow rates. The fact that a single α1A-adrenoceptor subtype is found in the prostatic and urethral smooth muscle cells led to the design of drugs with uroselectivity for this receptor subtype. Thus, alfuzosin and tamsulosin are uroselective α1- blockers and first-line drugs for treatment of BPH without utility in treating hypertension. SELECTIVE α2-BLOCKERS Yohimbine and Corynanthine. Yohimbine is a competitive and selective α2-blocker. The compounds are naturally occurring alkaloides and are found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root. Their structures resemble that of reserpine. The only difference between these two compounds is the relative stereochemistry. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ β-BLOCKERS β-Blockers are among the most widely employed antihypertensives and are also considered the first-line treatment for glaucoma. Structure–activity relationships - Most of β-blockers are in the chemical class of aryloxypropanolamines. - The first β-blocker is dichloroisoproterenol (DCI), differs structurally from ISO in that the agonist directing 3′,4′-di-OH groups have been replaced by two chloro groups. Unfortunately, DCI is not a pure antagonist but a partial agonist so, it was precluded as a clinically useful drug. - Pronethalol was the next important β-blocker developed. Although it had much less intrinsic sympathomimetic activity (ISA) than DCI, it was withdrawn from clinical testing because of reports that it caused thymic tumors in mice. - Propranolol, a close structural relative of pronethalol. It is the standard against which all other β-blockers are compared. Propranolol belongs to the group of β- blockers known as aryloxypropanolamines. - - University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ - The nature of the aromatic ring and its substituents that is the primary determinant of β-antagonistic activity. The aryl group also affects the absorption, excretion, and metabolism of the β-blockers. - The nature of the aromatic ring is also determines the β1-selectivity. One common structural feature of many cardioselective β1-blockers is the presence of a parasubstituent of sufficient size on the aromatic ring along with the absence of meta-substituents. Practolol is the prototypical example of a β1- blocker. Because it produced several toxic effects however, it is no longer in general use in most countries. - Like β-agonists, β-directing tert-butyl and isopropyl groups, are normally found on the amino function of the aryloxypropanolamine β-blockers. It must be a secondary amine for optimal activity. - For arylethanolamine adrenergic agonists, the β-OH substituted carbon must be in the R configuration for maximal direct activity. However, for β-blockers, the β-OH-substituted carbon must be in the S configuration for maximal β-blocking activity. - Propranolol is the most lipophilic drug among the available β-blockers, and thus it enters the CNS much better than the less lipophilic drug and so associated with more CNS side effects, such as dizziness, confusion, or depression. These side effects can be avoided, however, with the use of hydrophilic drugs, such as atenolol or nadolol. - The more lipophilic drugs are primarily cleared by the liver, and so their doses need to be adjusted in patients with liver disease. In contrast, the less lipophilic drugs are cleared by the kidney and so their doses need to be adjusted in patients with impaired renal function. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ NONSELECTIVE β-BLOCKERS (FIRST GENERATION) Propranolol (Inderal) It is the prototypical and nonselective β-blocker. It blocks the β1- and β2- receptors with equal affinity, lacks ISA, and does not block α-receptors. Currently, propranolol is approved for use in the United States for hypertension, cardiac arrhythmias, angina pectoris, postmyocardial infarction, hypertrophic cardiomyopathy, pheochromocytoma, migraine prophylaxis, and essential tremor. Because of its high lipophilicity and thus its ability to penetrate the CNS, propranolol has found use in treating anxiety and is under investigation for the treatment of a variety of other conditions, including schizophrenia, alcohol withdrawal syndrome, and aggressive behavior. Because it exhibits no selectivity for β1-receptors, it is contraindicated in the presence of conditions such as asthma and bronchitis. Other Nonselective β-Blockers. - Nadolol (antihypertensive and in longterm management of angina pectoris) - pindolol (antihypertensive) - penbutolol (antihypertensive) - carteolol (antihypertensive) - timolol (antihypertensive, prophylaxis of migraine headaches and in the therapy following myocardial infarction) - sotalol (antiarrhythmic in treating ventricular arrhythmias and atrial fibrillation because in addition to its β-adrenergic blocking activity, this agent blocks the inward K+ current that delays cardiac repolarization). - Carteolol, timolol, levobunolol, and metipranolol are used topically to treat open-angle glaucoma. These agents lower intraocular pressure with virtually no effect on pupil size or accommodation. They thus offer an advantage over many of the other drugs used in the treatment of glaucoma. - Pindolol possesses modest membrane-stabilizing activity and significant intrinsic β-agonistic activity. The β-blockers with partial agonistic activity cause less slowing of the resting heart rate than do agents without this University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ capability. The partial agonistic activity may be beneficial in patients who are likely to exhibit severe bradycardia or who have little cardiac reserve. β1-SELECTIVE BLOCKERS (SECOND GENERATION) Cardioselective β1-blockers are drugs that have a greater affinity for the β1- receptors of the heart than for β2-receptors in other tissues. Such cardioselective agents should provide two important therapeutic advantages. The first advantage should be the lack of a blocking effect on the β2-receptors in the bronchi so they are safe for use in patients who have bronchitis or bronchial asthma. The second advantage should be the absence of blockade of the vascular β2- receptors, which mediate vasodilation. This would be expected to reduce or eliminate the increase in peripheral resistance that sometimes occurs after the administration of nonselective β-blockers. Unfortunately, cardioselectivity is usually observed with β1-blockers at only relatively low doses. At normal therapeutic doses, much of the selectivity is lost. At present, the following β1-selective blockers are used therapeutically: acebutolol, atenolol (Tenormin), betaxolol, bisoprolol, esmolol, and metoprolol (Lopressor). All of these agents except esmolol are indicated for the treatment of hypertension. Atenolol and metoprolol are also approved for use in treating angina pectoris and in therapy following myocardial infarction. Betaxolol is the only β1-selective blocker indicated for the treatment of glaucoma. Esmolol was designed specifically to possess a very short DOA; it has an elimination half-life of 9 minutes. Its effects disappear within 20 to 30 minutes after the infusion is discontinued. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬ This agent is administered by continuous intravenous infusion for control of ventricular rate in patients with atrial flutter, atrial fibrillation, or sinus tachycardia. Its rapid onset and short DOA render it useful during surgery, after an operation, or during emergencies for short-term control of heart rates. Esmolol and acebutolol are also indicated for treating certain cardiac arrhythmias. Only acebutolol possesses ISA. However, this activity is very weak. Betaxolol, with a half-life ranging between 14 and 22 hours, has the longest DOA of the β1-selective blockers. Like propranolol, metoprolol has low bioavailability because of significant first-pass metabolism. β-BLOCKERS WITH α1-ANTAGONIST ACTIVITY (THIRD GENERATION) Several drugs have been developed that possess both β- and α-receptor– blocking activities within the same molecule. Two examples of such molecules are labetalol and carvedilol. As in the case of dobutamine, the arylalkyl group with nearby methyl group in these molecules is responsible for its α1-blocking activity. The bulky N-substituents and another substituted aromatic ring are responsible for its β-blocking activity. The rationale for labetalol use in the management of hypertension is that its α- receptor–blocking effects produce vasodilation and its β-receptor–blocking effects prevent the reflex tachycardia usually associated with vasodilation. Carvedilol has β-blocking activity is 10- to 100-fold of its α-blocking activity. This drug is also unique in that it possesses antioxidant activity and an antiproliferative effect on vascular smooth muscle cells. It thus has a neuroprotective effect and the ability to provide major cardiovascular organ protection. It is used in treating hypertension and congestive heart failure. University of Alkafeel Pharmaceutical Chemistry College of pharmacy 4th Year/1st Semester Lec. 10 ‫ ضرغام قاسم الخفاجي‬.‫د‬.‫أ‬