Integrated Level III Biomed. Chem. Michael B. Bolger
Dopamine Receptors, Agonists, and Parkinson’s Disease Objectives: 1.
2. 3.
4. 5. 6.
7.
At the end of the next two hours the student should be able to: List two types of dopamine receptor, know the anatomical distribution of these receptors, and explain the differences in their mechanism of coupling to adenylate cyclase. Recognize the structural formula of the three major rotamers of dopamine, and recall their names, and receptor binding selectivity. Give examples of three types of synthetic agonists which have some selectivity for dopamine receptor subtypes based on their rotameric conformation. Describe the rationale and limitations for anticholinergic and dopaminergic drug therapy in the treatment of Parkinson’s Disease. Recognize the structure of MPTP and its metabolites, and understand the biochemical basis of its selective toxicity in dopaminergic neurons. Identify the drugs in use today for the treatment of Parkinson’s disease by their trade or generic names and if given a structural formula be able to recall the appropriate drug action (i.e. agonist or antagonist) and neurotransmitter system(s) involved. Recognize the absolute stereochemistry of L-DOPA, and explain why LDOPA can enter the CNS whereas, dopamine and carbidopa cannot.
References: 1.
Principles of Medicinal Chemistry 4th ed., (1995), W.O. Foye, T.L. Lemke, and D.A. Williams, Chp. 13.
Three rotameric forms of Dopamine +
NH3
+
NH3 HO
HO
HO
+
NH3 HO
HO
HO beta rotamer D-1 & D-2 mixed
alpha rotamer D-2
gauche rotamer D-1
+
NH3
HO 7
8
1
+
HO
2
HO 6
HO 2-amino-5,6-dihydroxytetrahydronaphthalene (A-5,6-DTN) D-2 agonist (3H-Haldol) D-1 inactive (Vasodilation)
3 5
+
NH2
2-amino-6,7-dihydroxytetrahydronaphthalene (A-6,7-DTN)
+
N H
H
OH
+
HO SKB-38393 D-1 Agonist D-2 inactive
Mixed D-1 & D-2 agonist S
H3N
HO
4
F
O
NH3
HO
CH3
N
H
HO +
CH3 HO
OH
Haloperidol (HaldolTM) D-2 antagonist Schizophrenia
Cl
N H Pergolide Member of Clavine family of ergot alkyloids Mixed D-1 D-2 agonist
NH2 HO Cl Fenoldopam D-1 Agonist
Environmental Factors in Parkinson’s Etiology Meperidine CH3 H3C N
O O
H H3C N+
Street chemists working on meperidine analogs accidentally produced 3% contaminant. MPTP , 1-methyl-4-phenyl-1,2,3,4tetrahydro-pyridine CH3 N
+
MPTP can be converted to an oxidized form by MAO-B. The oxidized form is called MPDP. 1-methyl-4-phenyl-2,3-dihydro-pyridine CH3 N H3C
C CH
H
Deprenyl (Selegeline) 5 mg bid Selective MAO-B inhibitor CH3 N
+
MPDP is rapidly converted to the toxic metabolite MPP+. 1-methyl-4-phenyl-pyridine This compound has been shown to produce a disease state in humans that is identical to Parkinson’s Disease. +
H3C N
Paraquat (Herbicide)
+
N CH3
Dopaminergic Agonists pKa = 8.7 +
HO pKa = 9.9, 11.8 HO
NH3 H O
OH
Drug Interaction: Pyridoxine is a precursor of pyridoxal phosphate, a co-enzyme for L-amino acid decarboxylase. Excess Vit. B6 would eliminate the beneficial effects of L-DOPA
Levodopa (Larodopa, Dopar, Levopa) 3-hydroxy-L-tyrosine Initial Dose 100 mg tid,qid Side effects: nausea, vomiting, anorexia, postural hypotension, abnormal movements (chorea) OH OH
HO N
CH3
Pyridoxine (Vit. B6) pKa = 7.8 HO
+
NH2 NH2 CH3
Carbidopa A combination of fixed ratio 10/1 L-DOPA/Carbidopa = Sinemet Peripheral decarboxylase inhibitor
O HO OH Advantages of using Carbidopa with L-DOPA: 1. Optimally effective dose of L-DOPA can be reduced by 75% since more L-DOPA enters the CNS. 2. Nausea and vomiting from stimulation of medullary chemoreceptors are diminished. 3. Effective dose can be achieved more quickly because tolerance to the side effects does not need to be established. 4. Antagonism of L-DOPA by pyridoxine is avoided. 5. Diurnal variations in L-DOPA concentration are reduced. Side effects: 1. Abnormal involuntary movements occur earlier in the disease. 2. Adverse mental effects.
+
Amantadine (Symmetrel) Enhances dopamine synthesis and release. CNS stimulation is a prominent adverse effect. Headache, insomnia and anxiety are common; hallucinations and delirium are particularly problematic in older patients, particularly at higher doses. Livedo reticularis, a mottling appearance of the lower extremities, is a relatively benign adverse effect which occurs in the majority of patients taking amantadine on a chronic basis.
NH3
O
N-Peptide
H H
N pKa = 15 H
Bromocriptine (Parlodel) 2-bromo-α-ergocryptine D-2 agonist, D-1 antagonist.
pKa=6.6 N
Usual dose 50-60 mg/d Max dose: 150 mg/d Inhibits prolactin secretion (10 mg) Some visual and auditory hallucinations. May induce paranoid psychosis.
CH3
Br
CH3 Pramipexole (Mirapex)
D3 dopamine receptor full agonist with some activity at D2 and D4 sites. Bromocryptine is a partial D2 agonist and pergolide is a partial D1 and D2 agonist.
N H2N
N H
S
Ropinirole (Requip)TM 4-(2-(dipropylamino)ethyl-1,3-dihydro-2Hindol-2-one.
CH3 O HN
HO
N
+
CH3
D3 receptor agonist with some activity at D2 sites. The relevance of D-3 agonist activity is unknown.
Tolcapone (Tasmar) Catechol-O-methyl transferase inhibitor. Slows the breakdown of dopamine and levodopa. Crosses the BBB and has action in both periphery and CNS.
O HO HO
CH3
+
O
N
O
Relative Activity at Dopaminergic Receptors
