Foye's Principles of Medicinal Chemistry PDF

Chapter 2 Drug Design and Relationship of Functional Groups to Pharmacologic Activity...

Chapter 2 Drug Design and Relationship of Functional Groups to Pharmacologic Activity R O B I N M. Z AVO D AND J A M E S J. K N I T T E L Abbreviations HCl, hydrochloric acid PABA, p-aminobenzoic acid SAR, structure–activity relationship IV, intravenous QSAR, quantitative structure–activity USP, U.S. Pharmacopeia MW, molecular weight relationship NaOH, sodium hydroxide Medicinal chemistry is an interdisciplinary science at (Chapter 3). To design better medicinal agents, the rela- the intersection of organic chemistry, biochemistry (bio- tive contribution that each functional group (i.e., pharma- organic chemistry), computational chemistry, pharma- cophore) makes to the overall physicochemical properties cology, pharmacognosy, molecular biology, and physical of the molecule must be evaluated. Studies of this type chemistry. This branch of chemistry is involved with the involve modification of the molecule in a systematic fash- identification, design, synthesis, and development of new ion followed by a determination of how these changes drugs that are safe and suitable for therapeutic use in affect biologic activity. Such studies are referred to as humans and pets. It also includes the study of marketed structure–activity relationships (SARs)—that is, the rela- drugs, their biologic properties, and their quantitative tionship of how structural features of the molecule con- structure–activity relationships (QSARs). tribute to, or take away from, the desired biologic activity. Medicinal chemistry studies how chemical structure Because of the foundational nature of the content of influences biologic activity. As such, it is necessary to this chapter, there are numerous case studies presented understand not only the mechanism by which a drug throughout the chapter (as boxes), as well as at the end. exerts its effect, but also how the molecular and physico- In addition, a list of study questions at the conclusion chemical properties of the molecule influence the drug’s of—and unique to—this chapter provides further self- pharmacokinetics (absorption, distribution, metabolism, study material related to the subject of medicinal chem- toxicity, and elimination) and pharmacodynamics (what istry/drug design. the drug does to the body). The term “physicochemical properties” refers to how the functional groups present within a molecule influence its acid–base properties, INTRODUCTION water solubility, partition coefficient, crystal structure, ste- Chemical compounds, usually derived from plants and reochemistry, and ability to interact with biologic systems, other natural sources, have been used by humans for such as enzyme active sites (Chapter 8) and receptor sites thousands of years to alleviate pain, diarrhea, infection, Kaduse.com 29 Lemke_Chap02.indd 29 12/9/2011 4:12:11 AM  30 PART I / PRINCIPLES OF DRUG DISCOVERY and various other maladies. Until the 19th century, H3CO O these “remedies” were primarily crude preparations of H3C CH3 N OH plant material of unknown constitution. The revolution H 2 Cl in synthetic organic chemistry during the 19th century H produced a concerted effort toward identification of the O N H3C H structures of the active constituents of these naturally CH3O OH derived medicinals and synthesis of what were hoped to Tubocurarine be more efficacious agents. By determining the molecu- (muscle relaxant) lar structures of the active components of these complex CH3 mixtures, it was thought that a better understanding of N CH3 N CH3 how these components worked could be elucidated. X RELATIONSHIP BETWEEN MOLECULAR HO O OH HO O OH STRUCTURE AND BIOLOGIC ACTIVITY Early studies of the relationship between chemical struc- Morphine N-Methylmorphine ture and biologic activity were conducted by Crum-Brown (analgesic) (muscle relaxant) and Fraser (1) in 1869. They demonstrated that many compounds containing tertiary amine groups exhibited activity as muscle relaxants when converted to quaternary ammonium compounds. Molecules with widely differing X N N pharmacologic properties, such as strychnine (a convul- CH3 H3C CH3 N N sant), morphine (an analgesic), nicotine (a deterrent, insecticide), and atropine (an anticholinergic), could Nicotine N-Methylnicotine be converted to muscle relaxants with properties simi- (insecticide) (muscle relaxant) lar to those of tubocurarine when methylated (Fig. 2.1). Crum-Brown and Fraser therefore concluded that mus- cle relaxant activity required the presence of a quater- H3C H3C CH3 nary ammonium group within the structure. This initial N N X hypothesis was later disproven by the discovery of the natu- ral neurotransmitter and activator of muscle contraction, H H CH2OH CH2OH acetylcholine (Fig. 2.2). Even though Crum-Brown and O O Fraser’s initial hypothesis that related chemical structure with action as a muscle relaxant was incorrect, it demon- O O strated the concept that molecular structure influences N-Methylatropine Atropine the biologic activity of chemical entities and that altera- (mydriatic) (muscle relaxant) tions in structure produce changes in biologic action. With the discovery by Crum-Brown and Fraser that FIGURE 2.1 Effects of methylation on biologic activity. quaternary ammonium groups could produce molecules with muscle relaxant properties, scientists began to look for other functional groups that produce specific bio- exerted their effects was still a mystery. Using his obser- logic responses. At this time, it was thought that specific vations with regard to the staining behavior of micro- chemical groups, or nuclei (rings), were responsible for organisms, Ehrlich (4) developed the concept of drug specific biologic effects. This led to the postulate, that receptors. He postulated that certain “side chains” on the took some time to disprove, that “one chemical group surfaces of cells were “complementary” to the dyes (or gives one biological action” (2). Even after the discovery drug) and suggested that the two could therefore inter- of acetylcholine by Loewi and Navrati (3), which effec- act with one another. In the case of antimicrobial com- tively dispensed with Crum-Brown and Fraser’s concept pounds, interaction of the chemical with the cell surface of all quaternary ammonium compounds being muscle “side chains” produced a toxic effect. This concept was relaxants, this was still considered to be dogma and took the first description of what later became known as the a long time to refute. receptor hypothesis for explaining the biologic action of chemical entities. Ehrlich also discussed selectivity SELECTIVITY OF DRUG ACTION AND DRUG RECEPTORS O CH3 N Although the structures of many drugs or xenobiotics, or H3C O CH3 CH3 at least their functional group composition, were known at the start of the 20th century, how these compounds Kaduse.com FIGURE 2.2 Acetylcholine, a neurotransmitter and muscle relaxant. Lemke_Chap02.indd 30 12/9/2011 4:12:11 AM  CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 31 of drug action via the concept of a “magic bullet.” He action. One need only peruse the structures of drug suggested that this selectivity permitted eradication of molecules in a particular pharmacologic class to become disease states without significant harm coming to the convinced (e.g., histamine H1 antagonists, histamine H2 organism being treated (i.e., the patient). This was later antagonists, b-adrenergic antagonists). In the quest for modified by Albert (5) and today is referred to as “selec- better medicinal agents (drugs), it must be determined tive toxicity.” An example of poor selectivity was demon- which functional groups within a specific structure are strated when Ehrlich developed organic arsenicals that important for its pharmacologic activity and how these were toxic to trypanosomes as a result of their irrevers- groups can be modified to produce more potent, more ible reaction with thiol groups (-SH) on vital proteins. selective, and safer compounds. The formation of As–S bonds resulted in death to the An example of how different functional groups can target organism. Unfortunately these compounds were yield chemical entities with similar physicochemical toxic not only to the target organism, but also to the host properties is demonstrated by the sulfanilamide antibi- once certain blood levels of arsenic were achieved. otics. In Figure 2.3, the structures of sulfanilamide and The “paradox” that resulted after the discovery of p-aminobenzoic acid (PABA) are shown. In 1940, Woods acetylcholine—how one chemical group can produce (7) demonstrated that PABA reverses the antibacterial two different biologic effects (i.e., muscle relaxation and action of sulfanilamide (and other sulfonamide-based muscle contraction)—was explained by Ing (6) using the antibacterials) and that both PABA and sulfanilamide actions of acetylcholine and tubocurarine as his examples have similar steric and electronic properties. Both mol- (see also Chapter 9). Ing hypothesized that both acetyl- ecules contain acidic functional groups, with PABA con- choline and tubocurarine act at the same receptor, but taining an aromatic carboxylic acid and sulfanilamide an that one molecule fits to the receptor in a more comple- aromatic sulfonamide. When ionized at physiologic pH, mentary manner and “activates” it, causing muscle con- both compounds have a similar electronic configuration, traction. (Ing did not elaborate just how this activation and the distance between the ionized acid and the weakly occurred.) The blocking effect of the larger molecule, basic amino group is also very similar. It should be no tubocurarine, could be explained by its occupation of surprise that sulfanilamide acts as an antagonist to PABA part of the receptor, thereby preventing acetylcholine, metabolism in bacteria. the smaller molecule, from interacting with the receptor. With both molecules, the quaternary ammonium func- Biologic Targets for Drug Action tional group is a common structural feature and inter- In order for drug molecules to exhibit their pharmaco- acts with the same region of the receptor. If one closely logic activity, they must interact with a biologic target, examines the structures of other molecules with opposing typically a receptor, enzyme, nucleic acid, or excitable effects on the same pharmacologic system, this appears to membrane or other biopolymer. These interactions be a common theme: Molecules that block the effects of occur between the functional groups found in the drug natural neurotransmitters, such as norepinephrine, his- molecule and those found within each biologic target. tamine, dopamine, or serotonin for example are called The relative fit of each drug molecule with its target is antagonists and, are usually larger in size than the native a function of a number of physicochemical properties compound, which is not the case for antagonists of pep- including acid–base chemistry and related ionization, tide neurotransmitters and hormones such as cholecysto- functional group shape and size, and three-dimensional kinin, melanocortin, or substance P. Antagonists to these spatial orientation. The quality of this “fit” has a direct peptide molecules are usually smaller in size. However, impact on the biologic response produced. In this regardless of the type of neurotransmitter (biogenic chapter, functional group characteristics are discussed amine or peptide), both agonists and antagonists share as a means to better understand overall drug molecule common structural features with the neurotransmitter absorption, distribution, metabolism, and excretion, as that they influence. This provides support to the con- well as potential interaction with a biologic target. cept that the structure of a molecule, its composition and arrangement of functional groups, determines the type of pharmacologic effect that it possesses (i.e., SAR). For H H H H example, compounds that are muscle relaxants that act N N via the cholinergic nervous system possess a quaternary 6.7 A 6.9 A ammonium or protonated tertiary ammonium group and are larger than acetylcholine (compare acetylcholine in C O S O O O Fig. 2.2 with tubocurarine in Fig. 2.1). N H SARs are the underlying principle of medicinal chem- p-Aminobenzoic acid Sulfanilamide istry. Similar molecules exert similar biologic actions in a qualitative sense. A corollary to this is that structural ele- FIGURE 2.3 Ionized forms of p-aminobenzoic acid (PABA) and ments (functional groups) within a molecule most often sulfanilamide, with comparison of the distance between amine and contribute in an additive manner to the physicochemical ionized acids of each compound. Note how closely sulfanilamide properties of a molecule and, therefore, to its biologic resembles PABA. Kaduse.com Lemke_Chap02.indd 31 12/9/2011 4:12:12 AM  32 PART I / PRINCIPLES OF DRUG DISCOVERY PHYSICOCHEMICAL PROPERTIES OF DRUGS halogen ketone, neutral neutral O Acid–Base Properties F CO2H carboxylic acid The human body is 70 to 75% water, which amounts to aryl amine weak base approximately 51 to 55 L of water for a 160-lb (73-kg) N N aryl amine, weak base individual. For an average drug molecule with a molecu- HN lar weight of 200 g/mol and a dose of 20 mg, this leads alkyl amine to a solution concentration of approximately 2 × 10−6 basic M (2 mM). When considering the solution behavior FIGURE 2.4 Chemical structure of ciprofloxacin showing the vari- of a drug within the body, we are dealing with a dilute ous organic functional groups. solution, for which the Brönsted-Lowry (8) acid–base theory is most appropriate to explain and predict acid–base behavior. This is a very important concept in medicinal chemistry, because the acid–base proper- neutral functional groups are shown in Table 2.3. ties of drug molecules have a direct effect on absorp- Quaternary ammonium compounds are neither acidic tion, excretion, and compatibility with other drugs in nor basic and are not electrically neutral. Additional solution. According to the Brönsted-Lowry Theory, an information about the acid–base properties of the func- “acid” is any substance capable of yielding a proton tional groups listed in Tables 2.1 through 2.3 can be (H+), and a “base” is any substance capable of accepting found in Gennaro (9) and Lemke (10). Review of func- a proton. When an acid gives up a proton to a base, it is tional groups and their acid–base properties can also converted to its “conjugate base.” Similarly, when a base be found at www.duq.edu/pharmacy/faculty/harrold/ accepts a proton, it is converted to its “conjugate acid” basic-concepts-in-medicinal-chemistry.cfm. (Eqs. 2.1 and 2.2): A molecule can contain multiple functional groups with acid–base properties and, therefore, can possess CH3COOH + H2O  CH3COOΘ + H3O⊕ both acidic and basic character. For example, ciproflox- Acid Base Conjugate Conjugate acin (Fig. 2.4), a fluoroquinolone antibacterial agent, Eq. 2.1 contains a secondary alkylamine, two tertiary arylamines (acetic acid) (water) Base Acid (acetate) (hydronium ion) (aniline-like amines), and a carboxylic acid. The two aryl- amines are weakly basic and, therefore, do not contribute CH3 NH2 + H2O  CH3 NH3⊕ + ΘOH significantly to the acid–base properties of ciprofloxacin Eq. 2.2 Base Acid Conjugate Conjugate under physiologic conditions. Depending on the pH of (methylamine) (water) Acid Base the physiologic environment, this molecule will either (methylammionium ion) (hydroxide ion) accept a proton (secondary alkylamine), donate a proton (carboxylic acid), or both. Thus, it is described as ampho- Note that when an acidic functional group loses its teric (both acidic and basic) in nature. Figure 2.5 shows proton (often referred to as having undergone “dissocia- the acid–base behavior of ciprofloxacin in two different tion”), it is left with an extra electron and becomes nega- environments. Note that at a given pH (e.g., pH 1.0 to tively charged. This is the “ionized” form of the acid. The 3.5), only one of the functional groups (the alkylamine) ability of the ionized functional group to participate in an is significantly ionized. To be able to make this predic- ion-dipole interaction with water (see the Water Solubility tion, an appreciation for the relative acid–base strength of Drugs section) enhances its water solubility. Many of both the acidic and basic functional groups is required. functional groups behave as acids (Table 2.1). The ability Thus, one needs to know which acidic or basic functional to recognize these functional groups and their relative group within a molecule containing multiple functional acid strengths helps to predict absorption, distribution, groups is the strongest and which acidic or basic func- excretion, and potential incompatibilities between drugs. tional group is the weakest. The concept of pKa not only When a basic functional group is converted to the describes relative acid–base strength of functional groups, corresponding conjugate acid, it too becomes ionized. In this instance, however, the functional group becomes positively charged due to the extra proton. Most drugs O O that contain basic functional groups contain primary, F COO F CO2H secondary, and tertiary amines or imino amines, such as guanidines and amidines. Other functional groups N N N N that are basic are shown in Table 2.2. As with the acidic H N H N groups, it is important to become familiar with these H H functional groups and their relative strengths. Colon (pH 5.6–7) Stomach (pH 1.0–3.5) Functional groups that cannot give up or accept a pro- ton are considered to be “neutral” (or “nonelectrolytes”) FIGURE 2.5 Predominate forms of ciprofloxacin at two different with respect to their acid–base properties. Common locations within the gastrointestinal tract. Kaduse.com Lemke_Chap02.indd 32 12/9/2011 4:12:12 AM  CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 33 TABLE 2.1..ccoomm Common Acidic Organic Functional Groups and Their Ionized (Conjugate Base) Forms Acids (pKa) u u s s e e Conjugate Base Phenol (9-11) K Ka a d d R OH R O Phenolate Sulfonamide (9-10) ww.. O O Sulfonamidate wwww R S NH2 R S NH O O Imide (9-10) O O O O O O Imidate R N R' R N R' H R N R' Alkylthiol (10-11) R–SH Thiolate R S Thiophenol (9-10) SH Thiophenolate S R R N-Arylsulfonamide (6-7) O O N-Arylsulfonamidate m m H R S N R S N o o O O Sulfonimide (5-6) s s e e..cc O O O R' O O O R' O O O Sulfonimidate uu S R N R' S S dd H R N R' R N R' Alkylcarboxylic acid (5-6) K.. Kaa O R C OH O R C O Alkylcarboxylate ww wwww Arylcarboxylic acid (4-5) COOH COO Arylcarboxylate R R Sulfonic acid (0-1) O O O O Sulfonate S S R OH R O Acid strength increases as one moves down the table. but also allows one to calculate, for a given pH, the rela- Eq. 2.3 HCl + H2O  ClΘ + H3O⊕ tive percentages of the ionized and un-ionized forms of m m the drug. As stated earlier, this helps to predict relative NaOH + H2O  Na ⊕ + OHΘ + H2O o o water solubility, absorption, and excretion for a given Eq. 2.4 compound. Relative Acid Strength (pKa) sse e..c c Acids and bases of intermediate or weak strength, however, incompletely donate (dissociate) or accept a uu proton, and the equilibrium between the ionized and K K add Strong acids and bases completely donate (dissociate) a or accept a proton in aqueous solution to produce their un-ionized forms lies somewhere in the middle, such that all possible species can exist at any given time. Note.. respective conjugate bases and acids. For example, min- that in Equations 2.3 and 2.4, water acts as a base in eral acids, such as hydrochloric acid (HCl), or bases, such one instance and as an acid in the other. Water is there- ww as sodium hydroxide (NaOH), undergo 100% dissocia- fore amphoteric—that is, it can act as an acid or a base, wwww tion in water, with the equilibrium between the ionized depending on the prevailing pH of the solution. From and un-ionized forms shifted completely to the right a physiologic perspective, drug molecules are always (ionized), as shown in Equations 2.3 and 2.4: present as a dilute aqueous solution. The strongest base Kaduse.com Lemke_Chap02.indd 33 12/9/2011 4:12:15 AM  34 PART I / PRINCIPLES OF DRUG DISCOVERY TABLE 2.2 Common Basic Organic Functional Groups and Their Ionized (Conjugate Acid) Forms Base (pKa) Conjugate Acid Arylamine NH2 Arylammonium NH3 (9-11) R R Aromatic amine N NH Aromatic ammonium (5-6) R R Imine R C NH Iminium H (3-4) R C NH H Alkylamines NH Alkylammonium (20 - 10-11) NH2 (10 - 9-10) R NH2 R NH3 Amidine NH NH2 Amidinium (10-11) R NH2 R NH2 Guanidine NH Guanidinium NH2 (12-13) R N NH2 H R N NH2 H that is present is OH−, and the strongest acid is H3O+. (Eq. 2.5). Therefore, under physiologic conditions, alco- This is known as the “leveling effect” of water. Thus, hols are neutral with respect to acid–base properties: some functional groups that have acidic or basic charac- ter do not behave as such under physiologic conditions Eq. 2.5 CH3CH2OH + H2 CH3CH2O– + H3O⊕ in aqueous solution. For example, alkyl alcohols, such as ethyl alcohol, are not sufficiently acidic to become significantly ionized in an aqueous solution at a physi- Predicting the Degree of Ionization of a Molecule ologically pH. Water is not sufficiently basic to remove By knowing if there are acidic and/or basic func- the proton from ethyl alcohol to form the ethoxide ion tional groups present in a molecule, one can predict TABLE 2.3 Common Organic Functional Groups That are Considered Neutral Under Physiologic Conditions R–CH2–OH O O O O R R' S R' R' R O R O Alkyl alcohol Ether Ester Sulfonic acid ester O H R–C≡N R' N R N R" R NH2 R''' R R' Amide Diarylamine Nitrile Quaternary ammonium R' O S O O O R R' R N O S S R R' R R' R R' R" Amine oxide Ketone & Aldehyde Thioether Sulfoxide Sulfone Kaduse.com Lemke_Chap02.indd 34 12/9/2011 4:12:21 AM  CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 35 whether a molecule is going to be predominantly ion- ized or un-ionized at a given pH. To be able to quanti- tatively predict the degree of ionization of a molecule, O O O O O O the pKa values of each of the acidic and basic func- HN NH HN N HN N tional groups present and the pH of the environ- ment in which the molecule will be located must be O O O known. The magnitude of the pKa value is a measure Acid form Conjugate base of relative acid or base strength, and the Henderson- pKa 8.0 Hasselbalch equation (Eq. 2.6) can be used to calculate Question: At a pH of 7.4, what is the percent ionization of the percent ionization of a compound at a given pH amobarbital? (this equation was used to calculate the major forms of [acid] ciprofloxacin in Fig. 2.5): Answer: 8.0 = 7.4 + log [base] [acid form] [acid] Eq. 2.6 pK a = pH + log 0.6 = log [base form] [base] The key to understanding the use of the Henderson- 10 0.6 = [acid] 3.98 = Hasselbalch equation for calculating percent ionization [base] 1 is to realize that this equation relates a constant, pKa, to the ratio of the acidic form of a functional group to its % acid form = 3.98 x 100 = 79.9% 4.98 conjugate base form (and conversely, the conjugate acid form to its base). Because pKa is a constant for any given FIGURE 2.6 Calculation of percent ionization of amobarbital. functional group, the ratio of acid to conjugate base (or Calculation indicates that 80% of the molecules are in the acid conjugate acid to base) will determine the pH of the solu- (or protonated) form, leaving 20% in the conjugate base (ionized) tion. A sample calculation is shown in Figure 2.6 for the form. sedative hypnotic amobarbital. When dealing with a basic functional group, one must recognize the conjugate acid represents the ion- ized form of the functional group. Figure 2.7 shows as a result of an unequal sharing of electrons between the calculated percent ionization for the decongestant the two atoms within a covalent bond. This unequal shar- phenylpropanolamine. It is very important to under- ing of electrons only occurs when these two atoms have stand that for a base, the pKa refers to the conjugate significantly different electronegativities. When a per- acid or ionized form of the compound. To thoroughly manent dipole is present, a partial charge is associated comprehend this relationship, calculate the percent ionization of an acidic functional group and a basic functional group at different pH values and carefully OH observe the trend. OH NH2 NH3 CH3 CH3 Water Solubility of Drugs The solubility of a drug molecule in water greatly affects the routes of administration that are available, as well as Base form Conjugate acid form its absorption, distribution, and elimination. Two key pKa 9.4 concepts to keep in mind when considering the water (or Question: What is the % ionization of phenylpropanolamine at fat) solubility of a molecule are the potential for hydro- pH 7.4? gen bond formation and ionization of one or more func- [acid] Answer: 9.4 = 7.4 + log tional groups within the molecule. [base] [acid] 2.0 = log Hydrogen Bonds [base] Each functional group capable of donating or accepting a hydrogen bond contributes to the overall water solu- [acid] 100 102 = = bility of the compound and increases the hydrophilic [base] 1 (water-loving) nature of the molecule. Conversely, func- tional groups that cannot form hydrogen bonds do not % ionization = 100 x 100 = 99% 101 enhance hydrophilicity and will contribute to the hydro- phobic (water-fearing) nature of the molecule. Hydrogen FIGURE 2.7 Calculation of percent ionization of phenylpropanol- bonds are a special case of what are usually referred to as amine. Calculation indicates that 99% of the molecules are in the dipole–dipole interactions. A permanent dipole occurs acid form, which is the same as the percent ionization. Kaduse.com Lemke_Chap02.indd 35 12/9/2011 4:12:25 AM  36 PART I / PRINCIPLES OF DRUG DISCOVERY ACID–BASE CHEMISTRY/COMPATIBILITY ABSORPTION/ACID–BASE CASE CASES A long-distance truck driver comes into the pharmacy com- The intravenous (IV) technician in the hospital pharmacy gets plaining of seasonal allergies. He asks you to recommend an an order for a patient that includes the two drugs drawn below. agent that will act as an antihistamine but that will not cause She is unsure if she can mix the two drugs together in the same IV drowsiness. He regularly takes TUMS for indigestion due to the bag and is not certain how water soluble the agents are. bad food that he eats while on the road. H3C Cl O H N H3PO4 Cl O C N H H S CH3 H2PO4 N CH3 CH3O O COOH CH3 CH N N O O O CO2 K N OH H CH3 Penicillin V Potassium Codine phosphate Cetirizine (Zyrtec) Clemastine (Tavist) O 1. Penicillin V potassium is drawn in its salt form, whereas codeine phosphate is not. Modify the structure above to COOH show the salt form of codeine phosphate. Determine the acid–base character of the functional groups in the two N CH3 molecules drawn above as well as the salt form of codeine CH3 phosphate. Olopatadine (Patanol) 2. As originally drawn above, which of these two agents is more water soluble? Provide a rationale for your selection 1. Identify the functional groups present in Zyrtec and Tavist, that includes appropriate structural properties. Is the salt and evaluate the effect of each functional group on the form of codeine phosphate more or less water soluble than ability of the drug to cross lipophilic membranes (e.g., the free base form of the drug? Provide a rationale for your blood–brain barrier). Based on your assessment of each answer based on the structural properties of the salt form agent’s ability to cross the blood–brain barrier (and, there- of codeine phosphate. fore, potentially cause drowsiness), provide a rationale for 3. What is the chemical consequence of mixing aqueous solu- whether the truck driver should be taking Zyrtec or Tavist. tions of each drug in the same IV bag? Provide a rationale 2. Patanol is sold as an aqueous solution of the hydrochloride that includes an acid–base assessment. salt. Modify the structure present in the box to show the appropriate salt form of this agent. This agent is applied to the eye to relieve itching associated with allergies. Describe why this agent is soluble in water and what prop- Thus, for a hydrogen bonding interaction to occur, at erties make it able to be absorbed into the membranes that least one functional group must contain a dipole with surround the eye. an electropositive hydrogen. The hydrogen atom must 3. Consider the structural features of Zyrtec and Tavist. be covalently bound to an electronegative atom, such as In which compartment (stomach [pH 1] or intestine oxygen (O), nitrogen (N), sulfur (S), or selenium (Se). [pH 6 to 7]) will each of these two drugs be best absorbed? Of these four elements, only oxygen and nitrogen atoms 4. TUMS neutralizes stomach acid to pH 3.5. Based on your contribute significantly to the dipole, and we will there- answer to question 3, determine whether the truck driver fore concern ourselves only with the hydrogen-bonding will get the full antihistaminergic effect if he takes his antihistamine at the same time that he takes his TUMS. capability (specifically as hydrogen bond donors) of func- Provide a rationale for your answer. tional groups that contain a bond between oxygen and hydrogen atoms (e.g., alcohols) and functional groups that contain a bond between nitrogen and hydrogen atoms (e.g., primary and secondary amines and amides) with each of these atoms along a single bond (one atom (e.g., NH and CONH groups). has a partial negative charge, and one atom has a partial Even though the energy associated with each hydro- positive charge). The atom with a partial negative charge gen bond is small (1 to 10 kcal/mol/bond), it is the addi- has higher electron density than the other atom. When tive nature of multiple hydrogen bonds that contributes two functional groups that contain one or more per- to the overall water solubility of a given drug molecule. manent dipoles approach one another, they align such This type of interaction is also important in the interac- that the negative end of one dipole is electrostatically tion between a drug and its biologic target (e.g., recep- attracted to the positive end of the other. When the posi- tor). Figure 2.8 shows several types of hydrogen bonding tive end of the dipole is a hydrogen atom, this interac- interactions that can occur with a couple of functional tion is referred to as a “hydrogen bond” (or H-bond). groups and water. As a general rule, the more hydrogen Kaduse.com Lemke_Chap02.indd 36 12/9/2011 4:12:27 AM  CHAPTER 2 / DRUG DESIGN AND RELATIONSHIP OF FUNCTIONAL GROUPS TO PHARMACOLOGIC ACTIVITY 37 H H O H O H H δ+ H H H O O − H H δ O δ+ δ− N H O H H O H H+ δ+ O N δ R R' O HH H O H FIGURE 2.8 Examples of hydrogen bonding between water and FIGURE 2.9 Examples of ion–dipole interactions. hypothetical drug molecules. bonds that are possible between a drug molecule and the partially positively charged atom found in a perma- water, the greater the water solubility of the molecule. nent dipole (e.g., the hydrogen atoms in water) (Fig. 2.9). Table 2.4 lists several common functional groups and Organic salts are composed of a drug molecule in the number of hydrogen bonds in which they can poten- its ionized form and an oppositely charged counterion. tially participate. Note that this table does not take into For example, the salt of a carboxylic acid is composed account the possibility of intramolecular hydrogen of the carboxylate anion (ionized form of the functional bond formation. Each intramolecular hydrogen bond group) and a positively charged ion (e.g., Na+) and the decreases water solubility (and increases lipid solubility) salt of a secondary amine is composed of the ammonium because there is one less interaction possible with water. cation (ionized form of the functional group and a nega- tively charged ion; e.g., Cl−). Not all organic salts are very Ionization water soluble. To associate with enough water molecules In addition to the hydrogen-bonding capacity of a mole- to become soluble, the salt must be highly dissociable; in cule, another type of interaction plays an important role in other words, the cation and anion must be able to sepa- determining water solubility: the ion–dipole interaction. rate and interact independently with water molecules. This type of interaction can occur with organic salts. Ion– Highly dissociable salts are those formed from strong dipole interactions occur between either a cation and the acids with strong bases (e.g., sodium chloride), weak acids partially negatively charged atom found in a permanent with strong bases (e.g., sodium phenobarbital), or strong dipole (e.g., the oxygen atom in water) or an anion and acids with weak bases (e.g., atropine sulfate). Examples of strong acids (strong acids are 100% ionized in water [i.e., no ionization constants or pKa values of