Page 186 - Medicinal Chemistry Self Assessment

E
D
C
A
F
B

1. Using the se.
2. Based on their electronic induction.
3. Using the in pH environments of 1.7, 5.5, 6.0, 7.4, and 8.5.
Answer
The structure of haloperidol contains only one basic functional group and no acidic functional groups.

Tertiary amine
OH
N
F
Cl
O

4. Shown below is a structural analog can enhance the duration of haloperidol.

2.16 Haloperidol 175

5. Using the table below, identify the types of binding interactions that could be possible between the
boxed functional groups and a protein or enzyme receptor. Also identify amino acids present within
5. Using the table below ionizable functional groups.
a receptor or enzyme whose side chains could participate in the interactions that you identified.
Assume a plasma pH=7.4 for all ionizable functional groups.
C
B
D
A

Answer

Amino Acids Capable of Forming
Functional Group Types of Binding Interactions Specific Binding Interaction
A Ketone (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with carbon of ketone); Arg, Lys,
His* (with oxygen of ketone)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
B Tertiary amine (1) Ionic (1) Asp, Gln
(2) Ion–Dipole (as the Ion) (2) Ser, Thr, Tyr, Cys, Asn, Gln
C Tertiary hydroxyl (1) Ion–Dipole (as the Dipole) (1) Asp, Glu (with hydrogen of hydroxyl); Arg, Lys,
His* (with oxygen of hydroxyl)
(2) Dipole–Dipole (2) Ser, Thr, Tyr, Cys, Asn, Gln, His*
(3) Hydrogen Bond (Donor and/or Acceptor) (3) Ser, Thr, Tyr, Cys, Asn, Gln, Trp, His*
D Phenyl ring; aromatic ring; van der Waals; Hydrophobic Tyr, Phe, Trp (better interaction**); Val, Leu, Ile,
aromatic hydrocarbon Met, Ala
*The side chain of histidine is primarily unionized at a pH=7.4. The small fraction that is ionized could
form an ion–dipole interaction with a partially negative atom, while the unionized fraction can serve
as a hydrogen bond donor or acceptor. Additionally, it can serve as the dipole in an ion–dipole inter-
action.
**Stronger van der Waals interactions occur when aromatic rings interact with aromatic rings;
however, all of the listed amino acids could possibly interact with the indicated functional group.

6. Shown below is the structure of haloperidol and a list of five metabolic transformations. For each
metabolic transformation, indicate if it is a phase I or a phase II transformation and if haloperidol has
a functional group present to participate in the transformation. If you answer YES, then draw the
appropriate metabolite; if you answer NO, then provide a brief explanation as to why this metabolic
6. Shown below is the to perform with haloperidol.
transformation is not possible to perform with haloperidol.

Metabolic Pathways

A. Reduction

B. Sulfate Conjugation

C. Hydrolysis

D. Oxidative N-Dealkylation

E. Benzylic Oxidation

Answer
A. Reduction: Phase I, Yes

B. Sulfate conjugation is a phase II ation is low.

C. Hydrolysis is a phase I biotransformation.