Exam 2 Med Chem 1
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4 Points supporting Dopamine Hypothesis
• drugs that increase DA neurotransmission, induce or exacerbate schizophrenia • DA receptor density is increased in certain brain regions of untreated schizophrenics • many antipsychotic drugs strongly block D2 receptors in CNS • successful treatment of schizophrenia patients has been reported to change amount of HVA n CSF, plasma and urine.
Alpha 7 nicotinic type
Important memory, pain and addiction, cognition ability and auditory gating
1st gen order of binding (Phenothiazines)
D2/D1 >a1 = 5HT2 Take care of positive symptoms
1st gen order of binding (Butyrophenones)
D2>D1 = 5HT2>a1 Take care of positive symptoms
2nd gen order of binding
D2 = 5HT2 (improve negative symptoms)» D1>a1 Take care of positive and negative symptoms, but metabolism effects
3rd gen order of binding (D2 partial agonist)
Partial agonist D2 Partial agonism 5HT1a Antagonism of 5HT2a
blocking 5HT2a
By blocking 5HT2a in nigrostriatal tract, EPSEs are reduced, and blocking in frontal cortex reduces negative and cognitive symptoms
Phenothiazine Derivatives
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
Which Hydrogen more basic?
Want to have EDG, EWG will decrease basicity
How to make long acting neuroleptics
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.
SAR phenothiazine and dopamine
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
Optimal alkyl chain for antipsychotic effect
3 carbon
Antipsychotic potency EPS frequency
Piperazine > piperidines > aliphatics
Sedations Hypotensive effects
Aliphatics > piperidines > piperazine
Thioxanthene bioisosters
Remove Nitrogen and make double bond. Makes double bond and Cis will be stronger than trans
Metabolism of Haloperidol
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.
Haloperidol high incidence of tardive dyskinesia
forms HPTP then HPP+ goes form 0 double bond to 1-2-3. Metabolite form has charge and cannot leave brain now.
Benzamide
How to identify Benzo- group NH Double bond O
Dibenzazepine replacements
7 Member ring with Nitrogen. X can be substituted with… NH = dibenzodiazepine NH and Ring C thiophene = thienobenzodiazepine O = dibenzoxazepine S = dibenzothiazepine
Dibenzazepines
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
Benzisoxazoles
Nitrogen and Oxygen 5 member ring Metabolism Ring cleavage spontaneous in nature