Exam 2 Med Chem 1

Question 1

4 Points supporting Dopamine Hypothesis

Answer 1

1. drugs that increase DA neurotransmission, induce or exacerbate schizophrenia
2. DA receptor density is increased in certain brain regions of untreated schizophrenics
3. many antipsychotic drugs strongly block D2 receptors in CNS
4. successful treatment of schizophrenia patients has been reported to change amount of HVA n CSF, plasma and urine.

Question 2

Alpha 7 nicotinic type

Answer 2

Important memory, pain and addiction, cognition ability and auditory gating

Question 3

1st gen order of binding (Phenothiazines)

Answer 3

D2/D1 >a1 = 5HT2

Take care of positive symptoms

Question 4

1st gen order of binding (Butyrophenones)

Answer 4

D2>D1 = 5HT2>a1

Take care of positive symptoms

Question 5

2nd gen order of binding

Answer 5

D2 = 5HT2 (improve negative symptoms)» D1>a1

Take care of positive and negative symptoms, but metabolism effects

Question 6

3rd gen order of binding (D2 partial agonist)

Answer 6

Partial agonist D2
Partial agonism 5HT1a
Antagonism of 5HT2a

Question 7

blocking 5HT2a

Answer 7

By blocking 5HT2a in nigrostriatal tract, EPSEs are reduced, and blocking in frontal cortex reduces negative and cognitive symptoms

Question 8

Phenothiazine Derivatives

Answer 8

nonselective DA antagonist

Structural Properties:
Alkyl connector (3 C = optimal length)
3’ Amine
Phenothiazine Heterocycle

Lipophilic, can turn into salt due Nitrogen to have good water solubility

Question 9

Which Hydrogen more basic?

Answer 9

Want to have EDG, EWG will decrease basicity

Question 10

How to make long acting neuroleptics

Answer 10

Turn into Prodrug (nonactive form)

Make more lipophilic, so it stays longer in muscles where it forms depo and then it will get released slowly.

Turn OH or COOH into ester (esterase’s will cleave) and Adding more carbon can make last longer.

Question 11

SAR phenothiazine and dopamine

Answer 11

Preferred conformation of chlorpromazine, its side chain tile away from the midline towards the chlorine substituted ring

more electronegative atom, stronger the bond/pull towards it

Question 12

Optimal alkyl chain for antipsychotic effect

Answer 12

3 carbon

Question 13

Antipsychotic potency

EPS frequency

Answer 13

Piperazine > piperidines > aliphatics

Question 14

Sedations

Hypotensive effects

Answer 14

Aliphatics > piperidines > piperazine

Question 15

Thioxanthene bioisosters

Answer 15

Remove Nitrogen and make double bond.

Makes double bond and Cis will be stronger than trans

Question 16

Metabolism of Haloperidol

Answer 16

Ketone Group
Can be reduced into alcohol, turns into acid and loses 2 carbon atoms (oxidized) and then can do glucuronidation.

N group
Oxidative N-Dealkylation into 2 pieces, acid oxidized and loses 2 carbons and then can do glucuronidation.

Question 17

Haloperidol high incidence of tardive dyskinesia

Answer 17

forms HPTP then HPP+

goes form 0 double bond to 1-2-3.

Metabolite form has charge and cannot leave brain now.

Question 18

Benzamide

Answer 18

How to identify

Benzo- group
NH Double bond O

Question 19

Dibenzazepine replacements

Answer 19

7 Member ring with Nitrogen.

X can be substituted with…

NH = dibenzodiazepine
NH and Ring C thiophene = thienobenzodiazepine
O = dibenzoxazepine
S = dibenzothiazepine

Question 20

Dibenzazepines

Answer 20

lipophilic structure with very weak basic properties
C-11 Nitrogen center of basicity and allowing forming water soluble salt to make oral dosage

Metabolism:
Oxidation and Demethylation
Aromatic ring hydroxylation
N oxidation

Sulfoxides and Sulfunes with Sulfur ones

Glucuronidation can also happen

Question 21

Benzisoxazoles

Answer 21

Nitrogen and Oxygen 5 member ring

Metabolism
Ring cleavage spontaneous in nature