PHA 4140 - Gastrointestinal and Nutrition Section

Medicinal Chemistry Tutorial

Instructor: Patrick M. Woster, Ph.D.

Optional textbook: Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry, Ninth Edition, Edited by Jaime N. Delgado and William A. Remers, J.B. Lippincott, Philidelphia, 1991.

A variety of agents possess anticholinergic activity, as you will see below, including the major chemical classes of solanaceous alkaloids, synthetic anticholinergics and papaverine and its analogues. These compounds are useful in greater or lesser degree for three pharmacological results including:

Mydriatic effects - dilatation of the pupil of the eye and cycloplegia.

Antispasmodic effects - lowered tone and motility in the gastrointestinal and urinary tract.

Antisecretory effects - reduced salivation, persperation and gastric secretion.

The structure-activity relationships for these compounds depend on inclusion of general structural features including:

1. The cationic head - anticholinergic molecules attach to the acetylcholine (ACH) receptor by virtue of a charged nitrogen moiety, usually a protonated tertiary or quaternary ammonium group.

2. The hydroxyl group - although not required for activity, compounds which possess a hydroxyl substituent are generally more potent than the corresponding non-hydroxylated analogue. The position of the hydroxyl with respect to the nitrogen is reasonably critical.

3. The esteratic group - the most potent anticholinergic compounds possess an ester functionality that mimics the ester group in ACH.

4. The cyclic substituent - at least one bulky cyclic substituent (phenyl, thienyl, cyclohexyl, etc.) is present in almost all anticholinergic agents.

Naturally Occurring Anticholinergic Agents (Solanaceous Alkaloids)

The solanaceous alkaloids are naturally occurring anticholinergic compounds found in henbane (Hyoscyamus niger), deadly nightshade (Atropa belladonna) and jimson weed (Datura stramonium). The most common of these alkaloids are hyoscyamine, atropine and scopolamine, although there are other minor solanaceous constituents with insignificant pharmacological activity. These natural alkaloids are esters of the bicyclic amino alcohol tropine (3-hydroxytropane) and tropic acid. As shown below, tropine has two distinct conformers in which the hydroxyl group is axial (tropine) or equatorial (pseudotropine). However, tropine is not a chiral molecule, since it has a plane of symmetry. Tropic acid does possess a chiral center, however, and as such imparts a stereocenter to the solanaceous alkaloids. In general, the most potent of the solanaceous analogues have an axial tropine hydroxyl and are R-(-)-isomers with respect to the chiral center in the tropic acid moiety. The major solanaceous alkaloids and their tradenames appear in the figure below.

Because the solanaceous alkaloids are extremely potent, with human doses in the microgram range, the search for SAR correlations was focused on discovering agents with reduced side effects rather than with increased potency. Many of these side effects were due to CNS penetration, and as such a series of quaternary ammonium derivatives were synthesized. In general, these agents show fewer CNS manifestations, but are also more poorly absorbed and are of limited use in the eye. By far the most variety in the synthetic anticholinergics lies in the substitution of other acids for the tropic acid portion of the molecule. Analogues have been created with phenylacetic, mandelic, diphenylacetic, benzylic and xanthene-9-carboxylate acid moieties, and all have good activity. The pharmacophore for anticholinergic activity in the solanaceous and synthetic anticholinergic agents appears below. Noth the similarity of this pharmacophore to the naturally occurring neurotransmitter ACH.

Synthetic Anticholinergic Agents: Aminoalcohol Esters

A review of the commonly used synthetic anticholinergic agents reveals a marked departure from the rigid tropane ring structure. It is also apparent that introduction of a quaternary nitrogen in this series is successful, and in fact these analogues are slightly more potent as a group than the corresponding tertiary amines. Note also the variety of structure in the acid portion of these synthetic molecules.

Synthetic Anticholinergic Agents: Aminoalcohol Ethers

In the aminoalcohol ether series, the similarity between these agents and the antihistamines becomes apparrent. Compare, for example, the structures of chlorphenoxamine, orphenadrine and diphenhydramine. It should be readily apparent that the aminoalcohol ether anticholinergics possess a large component of antihistaminic activity, while the aminoalcohol ether antihistamines have considerable anticholinergic activity. The aminoalcohol ether anticholinergic agents are used primarily for their anti Parkinson effects.

Synthetic Anticholinergic Agents: Aminoalcohols

In the aminoalcohol series, it is apparent that the aminoester moiety is not required for anticholinergic activity, since the alcohol moiety in these compounds can serve as a suitable prosthetic for the carboxy functionality. In addition, all of these agents have a three carbon spacer between the amino and hydroxyl functionalities. The tertiary amine derivatives in this calss are useful for Parkinson's syndrome, while the quaternary derivatives (which do not enter the CNS) are used as antispasmodic and antisecretory agents.

Synthetic Anticholinergic Agents: Aminoamides and Miscellaneous Compounds

Aminoamides are similar in electronic character to the aminoalcohols, since the polar amide group replaces the alcohol functionality as a surrogate for the aminoester. Further modification of the basic anticholinergic structure has given rise to a variety of miscellaneous anticholinergics, as shown below.

Papaverine and Related Compounds

Papaverine and related compounds exert an antispasmodic effect not by a neurotrophic action, but by a direct myotropic effect on smooth muscle. They interfere with smooth muscle contraction by inhibiting the enzyme phosphodiesterase, and this spasmolytic effect is more pronounced in some muscles than others. All of these analogues are suitable substituted isoquinoline derivatives, as seen below.

H2 Receptor Antagonists

Early attempts to develop a histamine antagonist specific for the H2 receptor were focused on the observation that 4-methylhistamine was a potent and selective agonist at the then putative H2 receptor. The valuable lead compound N-guanylhistamine was subsequently discovered, which showed weak but definite H2 antagonism, but was also a partial agonist. By retaining the positively charged guanidine moiety and elongating the intermediate chain, the specific H2 antagonist burimamide was produced. Burimamide is poorly available orally, ans as such was not marketed.

Further research produced cimetidine (Tagamet¨), and then additional related products such as ranitidine, famotidine and nizatidine. Because of the relatively small number of analogues in this series, the SAR is not fully developed.

Prokinetic Agents

The so-called "prokinetic agents" act by increasing intestinal motility, thereby decreasing gastric emptying time. In the case of metaclopramide and domperidone, this appears to be due to antagonism of the peripheral and CNS effects of dopamine, sensitization of the GI tract to the effects of ACH, and a direct effect on intestinal smooth muscle. These two analogues are also effective antiemetics due to their effect on DA2 receptors. By contrast, the prokinetic effects of cisapride are more likely indirect, since the analogue appears to increase the release of endogenous ACH in the postganglionic nerve endings of the myenteric plexus in GI smooth muscle.

Proton Pump Inhibitors

The final step in the secretion of gastric acid is "proton pumping", which is mediated by the enzyme known as H+/K+ ATPase. This inhibition acts beyond the influence of second messengers in te parietal cell, and is independent of the action of secretogogues such as gastrin, histamine and ACH. Substituted benzimidazoles are potent proton pump inhibitors. One has been approved for use in the US, omeprazole (Prilosec¨). Interestingly, omeprazole rearranges (in the presence of acid) to a sulfenamide analogue, which acts as an irreversible inhibitor of the ATPase by forming a covalent disulfide bond with a crucial sulfhydryl group in the active site. The enantiomerically pure S-isomer, esomeprazole, has been marketed seperately as Nexium¨. Both omeprazole and esomeprazole can be used in "triple therapy" with amoxicillin and clarithromycin to eradicate H. pylori.

Prostaglandins and Cytoprotective Agents

It has been known for a number of years that prostaglandin synthetase is present in the gut wall, and that prostaglandins of the E and F series are synthesized and secreted in gastric juice. Prostaglandins (and in particular PGEs) can inhibit histamine-stimulated HCl release without interrupting mucosal flow, and are thus capable of protecting the mucosa, a phenomenon termed cytoprotection. Other effects include enhancement of mucosal blood flow, stimulation of bicarbonate release and increased mucus production. Because prostaglandins are short-lived intermediates in vivo, it is generally not possible to use these agents as cytoprotectants. However, there are now a number of analogues of PGE1 which are useful as cytoprotectants. The stable analogue misoprostol (Cytotec¨) was recently marketed for this purpose. Misoprostol has two structural features which make it more stable to metabolism than PGE1: the hydroxyl substituent is moved from the 15 to the 16 position, where it resides geminal to a methyl group, greatly reducing metabolism by oxidation, and it is administered as the methyl ester. The methyl ester is a pro-drug form which must be cleaved prior to activity. Misoprostol retains all of the cytoprotective attributes of PGE1. Additional cytoprotective agents related to misoprostol are in development, as shown below.

There is one additional cytoprotective agent which acts by a completely different mechanism. Sucralfate (Carafate¨) protects the gastric mucosa by forming a sticky, viscous gel that adheres to mucosal tissue and protects it from the action of gastric acid and pepsin. Sucralfate has no inherent acid-neutralizing activity.

Antacids

The most basic therapy for gastric hyperacidity (no pun intended!) is the use of basic inorganic salts as antacids. There are a variety of these agents available for over the counter use, and a discussion of there chemistry is beyond the scope of this course. Antacids are classified by their cationic metal, usually a sodium, magnesium or aluminum. Recall that sodium antacids should be avoided in hypertensive patients, that magnesium antacids can cause diarrhea, and that aluminum antacids can cause constipation.

Antidiarrheals

Commonly used antidiarrheals include the meperidine derivatives diphenoxylate (Lomotil¨) and loperamide (Imodium¨). Both are structurally related to 4-phenylpiperidine opioid analgesics, but have negligible opiate effects and a low abuse potential. These agents act by reducing the propulsive activity of the intestinal tract, a common side effect of the opiate analgetic agents. In fact, codeine may also be used for this purpose, but is less frequently used due to its addition liability and potential for abuse. Oral preparations containing kaolin and pectin (Kaopectate¨) or bismuth salts such as bismuth salicylate (Pepto-Bismol¨) are also commonly used.

Laxatives

Laxatives fall into one of several types:

Surfactants act by a detergent effect which enhances the mixing of fat and water to soften stools. The prime example of a surfactant laxative is dioctyl sodium sulfosuccinate (DSS, Colace¨).

Irritant laxatives act by direct contact with the gastric mucosa, and the resulting irritation causes a decrease in transit time. Examples of irritants are danthron (Modane¨), bisacodyl (Dulcolax¨), phenolphthalein, castor oil, and senna.

Bulk laxative act by increasing stool volume, and include psyllium-based laxatives such as Metamucil¨, methylcellulose containing laxatives and polycarbophil.

Lactulose, a simple disaccharide, is metabolized by colonic bacteria to lactate and small amounts of acetic and formic acids, resulting in acidification of the colonic contents and a resultant catharsis.

Antiflatulent Agents

Simethecone is the most commonly used antiflatulent, and acts by dispersing excess gas in the intestine before the patient has the opportunity to do so. It is a simple, methylated siloxane. Peppermint spirit and activated charcoal are also useful in this regard, but are less well tolerated.

Emetics and Antiemetics

A limited number of drugs are available for induction of vomiting in patients who have ingested toxic materials. The morphine analogue apomorphine can be used intravenously for this purpose. In addition, syrup of ipecac, a solution of plant alkaloids containing the emetic compound emetine, is used orally to induce emesis. Both of these drugs act by stimulation of the stomach and a direct effect on the chemotrigger zone.

A variety of phenothiazine and related analogues are useful for the treatment of nausea, and have a pronounced antiemetic effect. The phenothiazines have a direct effect on the chemotrigger zone in the CNS. Prochlorperazine (Compazine¨) is primarily used for this effect, since it has minimal neuroleptic activity. Prochlorperazine is not effective for preventing nausea due to motion sickness. Other compounds are more often used for this syndrome, including meclizine, dimenhydrinate and cyclizine, again due to thier effect on the chemotrigger zone. Scopolamine patches are also effective in the relief of motion sickness.

A number of miscellaneous compounds are also effective antiemetics. Ondansetron (Zofran¨) and granisitron (Kytril¨) are selective antagonists at the %-ht3 receptor, and are used to prevent emesis in patients receiving cancer chemotherapy. Dronabinol (Marinol¨), also known as THC, the active constituent of marijuana, is an effective antiemetic in chemotherapy patients, but the mechanism is complex and poorly understood. Trimethobenzamide (Tigan¨) is also useful for this purpose.

Drugs Used in the Treatment of Inflammatory Bowel Disease

The sulfonamide derivative sulfasalazine (Azulfidine¨) is widely used for prolonged treatment of ulcerative colitis. The drug is practically insoluble in water, and as such is poorly absorbed from the intestine and reaches the colon intact. In this location, bacterial azo-reductase enzymes cleave sulfasalazine to sulfapyridine and 5-aminosalicylic acid, which appears to be the active constituent. The mechanism of sulfasalazine involves the 5-aminosalacylic acid-mediated inhibition of prostaglandin synthesis in the colon, thus releiving the resultant inflammation. 5-Aminosalicylic acid is effective when administered alone, and is marketed seperately as mesalamine.

The antibacterial agent metronidazole (Flagyl¨) is also used for its effects in inflammatory bowel disease, primarily due to its bacteriocidal activity against Helicobacter pylori and other intestinal bacteria.

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