Stereochemistry and Biological Activity

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Questions and Answers

What are molecules with the same molecular formula but different spatial arrangements called?

Diastereomers

Stereoisomers (correct)

Isomers

Enantiomers

Which type of stereoisomerism involves non-superimposable mirror images?

Diastereomers

Geometric isomers

Enantiomers (correct)

Racemic mixtures

Which statement is true regarding the therapeutic properties of stereoisomers?

Stereoisomers cannot exhibit different biological activities.

Enantiomers always have the same effects in biological systems.

Only one stereoisomer of a racemic mixture may be active. (correct)

All stereoisomers have identical properties.

What is the first step in determining the absolute configuration of a stereogenic center?

Assign priorities to the ligands based on atomic number. Signup and view all the answers

If the sequence of ligands from 1 to 3 is counterclockwise during configuration assignment, what designation is given?

S (sinister) Signup and view all the answers

What type of isomers are E/Z alkene isomers considered?

Geometric isomers Signup and view all the answers

What is the lowest priority substituent in determining absolute configuration?

Hydrogen Signup and view all the answers

Which of the following correctly describes diastereomers?

They are non-superimposable and non-mirror images. Signup and view all the answers

What does a higher ability of an enantiomer to bind to receptor sites indicate about its potency?

The enantiomer acts on more binding sites. Signup and view all the answers

Which of the following statements about enantiomers is true?

Enantiomers differ in their interaction with polarized light. Signup and view all the answers

Which is the correct implication of the Easson-Stedman Hypothesis regarding drug-receptor interactions?

Three intermolecular interactions are necessary for drug efficacy. Signup and view all the answers

What does the R, S designation indicate about a compound?

It indicates the configuration of substituents around a chiral center. Signup and view all the answers

What characterizes a racemate?

An equal mixture of two enantiomers. Signup and view all the answers

How does the configuration (R or S) relate to optical rotation?

R and S have no relation to the direction of rotation. Signup and view all the answers

In the context of chirality, which statement about amino acids is true?

All amino acids are L-isomers and are chiral. Signup and view all the answers

When determining priority in the R and S nomenclature, which functional group has the highest priority?

-COOH Signup and view all the answers

Which is true about the enantiomers of dexchlorpheniramine?

The S-(+)-isomer is 200 times more potent than the R-(-)-isomer. Signup and view all the answers

What connection exists between the isomers of fluoxetine?

Only the S isomer demonstrates anti-migraine effects. Signup and view all the answers

What major problem did the drug thalidomide cause?

The S isomer resulted in significant toxicity. Signup and view all the answers

What distinguishes the enantiomers of dextropropoxyphene and levopropoxyphene?

Levopropoxyphene does not have analgesic properties. Signup and view all the answers

Which statement is correct regarding the pharmacological activities of enantiomers?

They can have opposite effects on biological activity. Signup and view all the answers

What is a potential drawback of using racemic drug mixtures?

Inactive components may lead to side effects. Signup and view all the answers

Which of the following statements is incorrect regarding the activities of nebivolol's isomers?

Neither isomer has therapeutic efficacy. Signup and view all the answers

Which enantiomer of picenadol acts as a narcotic antagonist?

(-)-isomer Signup and view all the answers

At a pH of 8.0, what percentage of molecules exist in the ionized form?

50% Signup and view all the answers

What percentage of amobarbital is in the unionized form at pH 2.0?

100% Signup and view all the answers

At a pH of 7.4, what is the ratio of [A-] to [HA] according to the calculations?

1:0.25 Signup and view all the answers

What pH value indicates that the acid form predominates to 99.7%?

5.5 Signup and view all the answers

What is the correct relationship between pH and pKa when pH is 6 log units below pKa?

Unionized form is dominant Signup and view all the answers

Which electronic effect is significant in determining the behavior of functional groups?

Resonance effect Signup and view all the answers

What is the total concentration of both the conjugate base and acid form when the pH is set at 7.4?

1.25 Signup and view all the answers

Which of the following statements is true regarding the ionized form at pH 7.4?

20% in ionized form Signup and view all the answers

What determines the acid-base properties of a functional group?

Protonation state Signup and view all the answers

Which property is NOT associated with the solubility effects of drugs?

Molecular symmetry Signup and view all the answers

If the pKa of a compound is 6, what is the pH where the acid form is fully ionized?

2.0 Signup and view all the answers

In the Henderson-Hasselbalch equation, what does pKa represent?

Dissociation constant of the acid Signup and view all the answers

Which factor influences the chirality of a molecule?

Absence of symmetry Signup and view all the answers

Which aspect is critical in predicting the behaviors of drugs in biological systems?

Functional group reactivity Signup and view all the answers

What is primarily affected by the steric effects of a functional group in drug design?

Shape and size interactions Signup and view all the answers

Which relationship in drug chemistry does the Henderson-Hasselbalch equation help explain?

Relationship between pH and ionization of drugs Signup and view all the answers

What is the percentage of ionization of phenylpropanolamine at a pH of 2.0?

99.99% Signup and view all the answers

How does urine alkalinization affect the excretion of acidic drugs like acetylsalicylic acid?

Increases the ionized state of the drug. Signup and view all the answers

At what pH does phenylpropanolamine display 99.7% ionization?

pH 5.5 Signup and view all the answers

What is a consequence of Ecstasy's charged character once it accepts a proton?

It becomes difficult to cross biological membranes. Signup and view all the answers

What is the primary reason that phenylpropanolamine is highly ionized in the stomach?

The pH of the stomach is low. Signup and view all the answers

What is the approximate pH required for urine alkalinization to enhance drug excretion?

Above 7.5 Signup and view all the answers

Why is there more than 50% nonionized drug in the plasma at pH 7.4?

The pH is slightly lower than the pKa. Signup and view all the answers

What happens to the ionized form of phenylpropanolamine at pH 8.0?

It becomes less ionized than at pH 2.0. Signup and view all the answers

Which enantiomer of dexchlorpheniramine is significantly more potent?

S-(+)-isomer Signup and view all the answers

What effect does the S-isomer of fluoxetine have compared to the racemic mixture?

It works effectively for anti-migraine treatment. Signup and view all the answers

Which statement regarding thalidomide is accurate?

The S-isomer was used to treat advanced leprosy. Signup and view all the answers

What is true about the pharmacological activities of the enantiomers of nebivolol?

One is a β-blocker and the other is a vasodilating agent. Signup and view all the answers

Which of the following statements is true regarding the isomers of dextropropoxyphene and levopropoxyphene?

Dextropropoxyphene is an analgesic, while levopropoxyphene is an antitussive agent. Signup and view all the answers

In how many cases can enantiomers have opposite effects?

Only in specific cases like picenadol. Signup and view all the answers

What challenge is associated with separating enantiomers in drug production?

It often requires complex chemical transformations. Signup and view all the answers

What is a major reason for selling drugs as racemic mixtures?

Combining isomers may enhance overall drug activity. Signup and view all the answers

What is the effect of the pH being below pKa on weak acids?

They remain un-ionized and can easily diffuse through membranes. Signup and view all the answers

In the environment of the stomach with a pH of 2, which statement is true regarding the absorption of drugs?

Most acids can diffuse through the membrane while most bases cannot. Signup and view all the answers

What characterizes a molecule with multiple asymmetric carbons concerning optical isomers?

It produces 2n optical isomers where n is the number of chiral centers. Signup and view all the answers

What is the outcome for acidic drugs when the pH is greater than the pKa?

They are predominantly un-ionized. Signup and view all the answers

Which property of functional groups helps determine a drug’s biological response?

Chemical properties of functional groups Signup and view all the answers

When analyzing the ionization of basic drugs, what occurs when the pH is lower than the pKa?

They predominately exist in an ionized form. Signup and view all the answers

How does the Henderson-Hasselbalch Equation relate to the ionization of drugs?

It calculates the percentage of ionization based on pH and pKa. Signup and view all the answers

What is the significance of chirality in drug design with respect to adverse effects?

Different enantiomers may have varying therapeutic and toxic effects. Signup and view all the answers

Study Notes

Stereochemistry and Biologic Activity

The Easson-Stedman Hypothesis states that drug-receptor interactions require a minimum of three points of contact for optimal binding.
Enantiomers are non-superimposable mirror images of each other.
A racemate is an equal mixture of two enantiomers.
All amino acids are chiral molecules and exist as L-isomers.
Proteins are also chiral and their interactions with enantiomers of chiral drugs can lead to different binding sites.

Types of Stereoisomers

Enantiomers: Non-superimposable mirror image isomers.
Diastereomers: Non-superimposable, non-mirror image isomers. They have more than one chiral center.
Geometric Isomers: Diastereomers that are E/Z alkene isomers.

Determining Absolute Configuration (R/S Convention)

The R/S convention is used to describe the spatial arrangement of ligands around a stereogenic center.
R (rectus): Clockwise order of ligands when viewed with the lowest priority group in the back.
S (sinister): Counterclockwise order of ligands when viewed with the lowest priority group in the back.

Assigning R/S Configuration

Assign priorities to the four ligands based on atomic number, with higher atomic number = higher priority.
Rotate the molecule so the lowest priority ligand is pointing away from the viewer.
Determine the direction of the remaining three ligands (1-3). Clockwise = R, Counterclockwise = S.

Enantiomeric Specificity in Biological Activity

One enantiomer may be more potent than the other: S-(+)-isomer of dexchlorpheniramine is 200 times more potent than the R-(-)-isomer.
Both enantiomers may be active, but one contributes to toxicity: R isomer of fluoxetine shows cardiac side effects while the S isomer is effective for anti-migraine effects.
One enantiomer may be responsible for side effects and toxicity: (S)-isomer of thalidomide caused birth defects, while the (R)-isomer was converted to (S)-isomer in vivo.
Enantiomers may have different therapeutic activities: Darvon (2R, 3S-(+)-dextropropoxyphene) is an analgesic, while Novrad (2S,3R-(-)-levopropoxyphene) is an antitussive.
Enantiomers may have opposite effects: (+)-isomer of picenadol is an opiate agonist, the (-)-isomer is an antagonist, and the racemate is a partial agonist.
Two enantiomers may have synergistic pharmacological activities: (+)-isomer of nebivolol is a -blocker, and the (-)-isomer is a vasodilating agent.

Separation of Enantiomers

It can be expensive to separate enantiomers.
About one-third of drugs are sold as racemic mixtures, even though only one enantiomer may be active or even cause adverse effects.

Functional Groups

Functional groups (FGs) are parts of compounds or drugs that provide specific characteristics and behaviors, allowing them to produce biological responses.
FGs influence a compound's or drug's properties through electronic, steric, and acid-base effects.
Electronic Effects: Include resonance and inductive effects which influence the distribution of electron density within a molecule. Resonance involves the delocalization of electrons, while inductive effects involve the polarization of electron density.
Steric Effects: Relate to the spatial arrangement of atoms and functional groups, influencing the molecule's shape and how it interacts with other molecules.
Acid-base Properties: Determine how a compound interacts with protons (H+). Acidic FGs donate protons, while basic FGs accept protons.

Henderson-Hasselbalch Equation

This equation relates the pH of a solution to the pKa of a weak acid or base and the ratio of ionized to un-ionized forms.
Weak Acids: The equation is pKa = pH + log ([acid]/[conjugate base]), where pKa is the negative logarithm of the acid dissociation constant.
Weak Bases: The equation is pH = pKa + log ([base]/[conjugate acid]).

Chirality and Stereochemistry

The orientation of functional groups in three-dimensional space defines a molecule's stereochemistry.
Asymmetric Carbon (chiral carbon): A carbon atom bonded to four distinct substituents.
Molecules with 'n' asymmetric carbons result in 2^n optical isomers.
Enantiomers: Stereoisomers that are non-superimposable mirror images of each other.
Enantiomers can have different biological activities:
- One enantiomer can be significantly more potent than the other.
- Both isomers could be active but only one contributes to toxicity.
- One enantiomer could produce undesirable side effects and toxicity.
- Enantiomers can have opposite therapeutic activities.
- Two enantiomers can have synergistic pharmacological activities.

Separation of Enantiomers

About a third of drugs are sold as racemic mixtures, containing equal amounts of both enantiomers.
Separating enantiomers can be costly.
Inactive enantiomers might contribute to side effects.

Acid-base Properties and Absorption

Ionized forms of drugs have difficulty crossing biological membranes, while un-ionized forms can easily diffuse.
Weak acids: At pH below their pKa, they are predominantly in the un-ionized form, readily crossing membranes.
Weak bases: At pH below their pKa, they are predominantly in the ionized form, making membrane crossing difficult.
The pH of the environment influences a drug's absorption. For example, in the stomach (low pH), weak acids are absorbed, while weak bases are less absorbed.

Pharmacist Alert

Drug Trapping in the Stomach: Weakly basic drugs, like morphine, are trapped in the stomach due to ionization.
Urine Alkalinization: Increasing urine pH above the pKa increases the ionized form of acidic drugs, promoting their excretion. For instance, aspirin (acetylsalicylic acid) excretion is enhanced by urine alkalinization.
Urine Alkalinization for Poison Elimination: Administering sodium bicarbonate or oral tablets to raise urine pH (>7.5) can enhance the elimination of certain poisons like mecoprop, methotrexate, phenobarbital, and salicylate.
Ecstasy (MDMA) Absorption: Ecstasy, a weak base, is poorly absorbed in the stomach due to ionization. In the small intestine (more alkaline), it readily crosses membranes.
Rule of Thumb for Absorption: Weak acids are more likely to be absorbed in a low pH environment (stomach), while weak bases are more likely to be absorbed in a higher pH environment (small intestine).
Percentage of Ionization: The Henderson-Hasselbalch equation can be used to calculate the percentage of ionization for a drug at a specific pH.

Summary of Key Points

Functional groups determine the properties and biological activity of a compound or drug.
The Henderson-Hasselbalch equation predicts the ionization state of a drug based on its pKa and the pH of the surrounding environment.
Chirality plays a crucial role in drug activity and side effects.
Enantiomers can exhibit different biological properties, including potency, toxicity, and therapeutic effects.
The pH of the environment influences drug absorption, with weak acids favored in low pH environments, and weak bases favored in high pH environments.

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Description

This quiz covers essential concepts in stereochemistry, focusing on drug-receptor interactions and the classification of stereoisomers. Explore the Easson-Stedman Hypothesis, enantiomers, diastereomers, and the R/S convention for determining absolute configuration. Test your knowledge on how these concepts apply to biologically active compounds.