Drugs Acting on CNS Depressant Drugs

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 1 2 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

• drugs are used to manage psychosis:  Schizophrenia. Antipsychotic Drugs  Bipolar disorder. • Idiopathic . (Major Tranquilizers) • Increased dopamine activity (mesolimbic). • D2-antagonism is the major mechanism. • Extrapyramidal symptoms (typical drugs). • Unsteady Parkinson’s disease-type movement.

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 3 4 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) • The major 4 dopamine pathways in the brain: • Other CNS receptors systems are involved:  Mesolimbic (Behavioral response).  Acetylcholine.  Nigrostriatal (Production of movement).  Histamine.  Mesocortical (Motivation & Emotional  Norepinephrine . response).  Serotonin.  Tuberoinfundibular (Prolactin secretion). • Specially for atypical drugs.

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 5 6 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Classification of Antipsychotic Agents Development of Typical

• Typical:  & derivatives .  Butyrophenone derivatives . • Atypical:  derivatives .  Benzazepine derivatives .  Benzisoxazole & benzisothiazole derivatives .

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 7 8 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Cont.

C2H5 CH3 CH3 S NCH2CH2N NCH2CH2N NCH2CH2N C2H5 CH3CH2 CH3 CH3 VI IV V diethazine ethylenediamines tripelennamine (anti-Parkinson) (antihistaminic) (antihistaminic)

Cl

CH3 CH3 S NCH2 CH N S NCH2 CH2 CH2 N CH3 CH3 CH3 VII VIII promethazine chlorpromethazine (antihistaminic) (antipsychotic) sedative 1950 Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 9 10 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Structure-Activity Relationships Structure-Activity Relationships

• Dopamine trans –rotamer conformation. • Favored.

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 11 12 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 13 14 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 15 16 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Structure-Activity Relationships Metabolism of

S S

N Cl N CF3 O O

CH2 CH2 CH2 NN CH2 CH2 OC (CH2)8CH3 CH2 CH2 CH2 NNCH2 CH2 OC (CH2)5CH3

Perphenazine enanthate enanthate

S S

N SO2N(CH3)2 N CF3 O O

H CH2 CH2 NN CH2 CH2 OC (CH2)8CH3 CH2 CH2 CH2 NNCH2 CH2 OC (CH2)8CH3

Flupenthixol Fluphenazine decanoate decanoate • Long duration! • More than 30 metabolites! • Route of administration? Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 17 18 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Development of Butyrophenone Synthesis of Chlorpromazine Neuroleptics (typical)

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 19 20 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Development of Butyrophenone COOC2H5 Neuroleptics N

COOC2H5 O H3C N

butyrophenone analog meperidine 1950s (analgesic) O COOC2H5 COOC2H5 OH N N F N O O

analog butyrophenone analog (200-fold) (chropromazine action) 1950s 1957 Cl Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 21 22 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 23 24 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 25 26 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 27 28 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 29 30 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Structure-Activity Relationships Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 31 32 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Structure-Activity Relationships

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 33 34 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Metabolism of Haloperidol Synthesis of Haloperidol

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 35 36 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Benzamide Derivatives (atypical) Benzamide Derivatives

• Local anesthetic & antiemetic properties. • Local anesthetic & antiemetic properties. • Neuroleptic properties & Anticholinesterase • Neuroleptic properties & Anticholinesterase properties. properties. • • Blockade of D2/D 3,M3, 5-HT 1A, 5-HT 3. Blockade of D2/D 3,M3, 5-HT 1A, 5-HT 3. Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 37 38 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

H N(C H ) H H H 2 5 H R N H R N H R N H

H N(C2H5) H H (C2H5)N H H H H

CH3O O R =

H2N Cl

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 39 40 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014) Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 41 42 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)

Benzisoxazole & Benzisothiazole Benzazepine Derivatives (atypical) Derivatives (atypical)

Associate Prof. Magdi A. Mohamed, Faculty Associate Prof. Magdi A. Mohamed, Faculty 43 44 of Pharmacy, University of Khartoum (2014) of Pharmacy, University of Khartoum (2014)