Document Detail


Efficacy and potency comparisons among aporphine enantiomers: effects on dopamine neurons in substantia nigra of rat.
MedLine Citation:
PMID:  2184376     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Extracellular single unit recording studies were carried out on male rats to determine the responses of dopamine neurons of the substantia nigra to intravenous administration of the enantiomers of the aporphine congeners, apomorphine (APO), N-n-propylnorapomorphine (NPA) and 11-hydroxy-N-n-propylnorapomorphine (11-OH-NPa). The R-(-)-configuration was found to be the most critical determinant of the efficacy and potency of the agonists. All R-(-)-aporphines were full agonists, able to inhibit completely firing of dopamine cells. The order of potencies, defined by the ID50s, was: (-)NPA, 2.0 +/- 0.4 nmol/kg greater than (-)11-OH-NPa, 4.7 +/- 0.7 nmol/kg greater than (-)APO, 18.0 +/- 4.0 nmol/kg. Thus, potency was increased about 9-fold by replacing the 6N methyl of APO with an n-propyl (NPA). Conversely, the 10-hydroxy was not essential for agonist activity (11-OH-NPa) but could increase potency. In the S-(+)-series responses varied. (+)N-n-Propylnorapomorphine exhibited agonist properties and could fully inhibit dopamine cells, but its potency was low (ID50 1550 nmol/kg); (+)APO produced only slight but significant decreases in firing at large (8434 nmol/kg) doses and (+)11-OH-NPa was devoid of efficacy in that it caused no significant changes in firing. Despite their loss of efficacy and potency, the (+)-enantiomers apparently did retain affinity for DA receptors, since they could act as antagonists if given before (-)APO or NPA. These findings suggest that stereochemical conformation and key structural elements of the aporphines are interactive in determining agonist efficacy and potency within this physiological test system.
Authors:
L P Martin; R F Cox; B L Waszczak
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neuropharmacology     Volume:  29     ISSN:  0028-3908     ISO Abbreviation:  Neuropharmacology     Publication Date:  1990 Feb 
Date Detail:
Created Date:  1990-05-30     Completed Date:  1990-05-30     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0236217     Medline TA:  Neuropharmacology     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  135-43     Citation Subset:  IM    
Affiliation:
Pharmacology Section, Northeastern University, College of Pharmacy and Allied Health Professions, Boston, Massachusetts 02115.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aporphines / pharmacology*
Dopamine / physiology*
Dose-Response Relationship, Drug
Electrodes
Male
Neurons / drug effects,  metabolism*
Rats
Rats, Inbred Strains
Stereoisomerism
Stereotaxic Techniques
Substantia Nigra / cytology,  drug effects,  metabolism*
Grant Support
ID/Acronym/Agency:
NS 23541/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Aporphines

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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