Neuropharmacology and stereochemistry of dopamine receptor agonist and antagonist enantiomeric pairs.
Neuropharmacological evaluation of the R and S isomers of 11-hydroxy-N-n-propylnoraporphine (11-OH-NPa) supports the impression that the 11-OH group in aporphines (analogous to the meta hydroxyl of dopamine, DA) is sufficient to confer high affinity and activity at DA receptors. As in the case of the catechol congeners, (R)-apomorphine (APO) and (R)-N-n-propylnorapomorphine (NPA), (R)-11-OH-NPa is a potent DA agonist while, like (S)-NPA, (S)-11-OH-NPa is a DA antagonist. Thus, (R) and (S)-11-OH-NPa are an additional pair of compounds in which one enantiomer is a DA agonist and the other an antagonist. Other analogous pairs are the enantiomers of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP), and cis-1-methyl-5-hydroxy-2-(di-n-propylamino)tetralin (5-OH-MDAT). All contain a meta hydroxyphenyl, an N-n-propyl, and a phenethylamine moiety which can be superimposed in a consistent way to discriminate the DA agonists from the antagonists, with the key feature in this discrimination being the direction of the ammonium hydrogen. An energy penalty must be incurred by 3-PPP to assume the required conformations and it may account for the relatively low potency of the 3-PPP enantiomers. This analysis supports the view that rigid analogs of flexible compounds when "frozen" in their biologically active conformation exhibit higher affinity interactions with the receptor.
Neumeyer
J L
JL
Section of Medicinal Chemistry, College of Pharmacy and Allied Health Professions, Northeastern University, Boston, MA 02115.
Froimowitz
M
M
Baldessarini
R J
RJ
Campbell
A
A
Gao
Y G
YG
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000031:analogs & derivatives*; D001060:Aporphines / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D008968:Molecular Conformation; D009281:Naphthalenes / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D001060:Aporphines; D009281:Naphthalenes; D010880:Piperidines; D011954:Receptors, Dopamine; D013764:Tetrahydronaphthalenes; C008081:11-hydroxy-N-(n-propyl)noraporphine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C045972:5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin; C026539:preclamol; D004298:Dopamine