1. Benzodiazepine and benzodiazepine-like drugs
PHRM 4060 Spring 2010
Benzodiazepine and benzodiazepine-like drugs 1 2 3 4 5 6 7 9 8
 Used as an alternative to benzodiazapines.

2. Updates www.pharmwiki.org
Office Hours- Friday 5-6p or Facebook (Dr. Arthur Roberts)
Room 424 in Pharmacy South

3. Outline Structure of Benzodiazepine (BZD) Characteristics
GABAA receptor and agonists
BZD SAR
BZD Metabolism
Non-BZD – w site agonist

4. 1 2 3 4 5 6 7
diazepine 9 8
benzene
benzo-di-azepine
azepine

5. Benzodiazepines GABA GABAA receptor Properties Sedation/hypnosis
PHRM 4060 Spring 2010
Benzodiazepines
GABA GABAA receptor
Properties
Sedation/hypnosis
Decreased anxiety
Anterograde amnesia (negative)
Anticonvulsant
Muscle relaxation
g-aminobutyric acid
(GABA analog)
Lyrica (GABA analog)

6. Benzodiazepines Therapeutic and Efficacy half life
PHRM 4060 Spring 2010
Benzodiazepines
Therapeutic and Efficacy half life
Anticonvulsants  long half-lives
CNS and Status epilepticus
Sleep  short half-lives
Anti-anxiety  long half-life, except aprazolam (Xanax) ~12 hours
alprazolam
(Xanax)

7. Examples Anticonvulsant Sleep Anti-anxiety clonazepam (Klonopin)
PHRM 4060 Spring 2010
Examples
Anticonvulsant
Sleep
Anti-anxiety
Elimination half life is Italics
clonazepam (Klonopin)
18-50 hours
triazolam (Halcion)
hours
diazepam (Valium)
hours
(active desmethyl metabolite)

8. A B (w site) D C g-aminobutyric acid (GABA) PHRM 4060 Spring 2010
2 GABA need to bindhttp://pubs.niaaa.nih.gov/publications/arh314/ htm
Chloride Conductance

9. KD’s of GABAA agonists Compound Diazepam 16 nM 16 17 15 Clonazepam 1.3
PHRM 4060 Spring 2010
KD’s of GABAA agonists
Compound a1 a2 a3 a5
Diazepam
16 nM 16 17 15
Clonazepam
1.3
1.7 2 -
Triazolam
1.8
1.2 3 Ro
2.6
0.24
Zolpidem
291
357
>15000 L 48 27 24
0.45
-weak partial inverse agonist
–a5 inverse agonist

10. Rules a1-a3 and a5 non-selective a1-a3 anticonvulsant
a1 sedation and hypnosis
a2 and a5 anxiolytic

11. Benzodiazepines SAR 1,4 benzodiazepine
PHRM 4060 Spring 2010
Benzodiazepines SAR 1 7 4
1,4 benzodiazepine
Electron withdrawing group (EWG)  7 position,
X= Cl < Br < F < CN < CF3 < NO2
Stronger EWG give more potent compounds

12. Example clonazepam (Klonopin) oxazepam (Serax) equiv. dose = 0.5 mg
PHRM 4060 Spring 2010
Example
clonazepam (Klonopin)
equiv. dose = 0.5 mg
oxazepam (Serax)
equiv. dose = 20 mg

13. Benzodiazepines SAR (6-9)
>
>

14. Benzodiazepines SAR (5)
>
ortho
para

15. Benzodiazepines SAR (5)
X aromatic ring  antagonist

16. Flumazenil (Anexate) GABAA receptor antagonist BZD overdoses
PHRM 4060 Spring 2010
Flumazenil (Anexate) 5
GABAA receptor antagonist
BZD overdoses
hypersomnia
X Patent
Liver  Carboxylic Acid Metabolite + Glucuronidation
ADR: headache and insomnia
BZ=Benzodiazapine
If you have liver disease
Flumazenil is the only GABAA receptor antagonist on the market
The patent has expired for it.

17. Benzodiazepines SAR (3-5)
PHRM 4060 Spring 2010
Benzodiazepines SAR (3-5)
decreased potency; change in conformation of the diazepine ring

18. Benzodiazepines SAR (3)
potency
half life
prodrug
UGTs

19. Benzodiazepines SAR (3) (Prodrug)
PHRM 4060 Spring 2010
Benzodiazepines SAR (3) (Prodrug) H H H Cl Cl
decarboxylase
clorazepate
desmethyldiazepam (active)
(a.k.a. nordazepam (Nordaz))

20. Benzodiazepines SAR (2)
>

21. Benzodiazepines SAR (1)
PHRM 4060 Spring 2010
Benzodiazepines SAR (1)
N1 substitution should be small, H, Methyl, Ethyl as in 1-3
Benzyl is more bulky and would be less active as is but would be converted to 3 on metabolism

22. Benzodiazepines SAR (1,2-imidazo ring)
PHRM 4060 Spring 2010
Benzodiazepines SAR (1,2-imidazo ring) 2 1 10 3 9 4 8 5 7 6
short half-lives; oxidation of methyl to alcohol and glucuorination

23. Examples triazolam midazolam alprazolam (Xanax) PHRM 4060 Spring 2010
– lethal injection - open ring form under acidic conditions
- used to treat insomnia and jet lag; President George W. Bush used it.
- anti-anxiety
triazolam
midazolam
alprazolam (Xanax)

24. MeTabolism

25. halazepam diazepam (Valium) prazepam clorazepate PHRM 4060 Spring 2010

26. PHRM 4060 Spring 2010 OH
midazolam
a-hydroxymethyl midazolam

27. Non-benzodiazepines (Non-BZD)
imidazopyridines
pyrazolopyrimidine
cyclopyrrolones

28. Non-BZD site agonist
PHRM 4060 Spring 2010
Non-BZD site agonist
Zolpidem (Ambien) - Insomnia
Rapid absorption GI, but food delays 30 min
CYP3A4 inactivates
Duration 6-8 hours
half-life 2.5 hours (Liver disease)
92% protein bound
ADR: amnesia
Used as a “Date Rape Drug”

29. Non-BZD site agonist
PHRM 4060 Spring 2010
Non-BZD site agonist O 5
Zaleplon (Sonata) - Insomnia
30% bioavailable. Onset 1hr food delays
Aldehyde oxidase  inactive metabolite (X CYP450)
half-life 1 hour; duration 6-8 h
60% protein bound
ADR Amnesia

30. Non-BZD site agonist
PHRM 4060 Spring 2010
Non-BZD site agonist H
Eszopiclone (Lunesta)- Insomnia
S isomer of racemic zopiclone (EU denied patent)
Rapid absorption peak in 1 hour, but food delays
50% protein binding
Metabolized by CYP3A4 and CYP2E1
active–desmethyl
inactive-N-oxide
Half-life 6h
ADR: headache, hallucinations anxiety, amnesia, Unpleasant taste (34%)
EU denied patent because it was too similar to Zopliclone

31. Huedo-Medina, T. B. , Kirsch, I. , Middlemass, J. , Klonizakis, M
Huedo-Medina, T. B., Kirsch, I., Middlemass, J., Klonizakis, M., and Siriwardena, A. N. (2012) Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration, BMJ 345, e8343.

32. Alternative: Ramelteon (Rozerem)
PHRM 4060 Spring 2010
Alternative: Ramelteon (Rozerem)
1/10 M-II
Melatonin
Insomnia
Melatonin receptor (MT1 and MT2) agonist (No GABAA)
sleep-wake cycle and circadian rhythm
Onset 30 mins
Bioavailable is 1.8%
Metabolized by CYP1A2, first pass converts to active metabolite M-II
Food delays absorption
82% protein bound
ADR: headache, depression, insomnia worsened
The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17 – 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20 – 100 fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes.
 Ramelteon not effective.

33. Outline Structure of Benzodiazepine (BZD) Characteristics
GABAA receptor and agonists
BZD SAR
BZD Metabolism
Non-BZD – w site agonist