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Dopamine receptor agonist activity of U‐66444B and its enantiomers: Evaluation of functional, biochemical, and pharmacokinetic properties
Author(s) -
von Voigtlander Philip F.,
Althaus John S.,
Ochoa Marlene Camacho,
Neff Gary L.
Publication year - 1989
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430170108
Subject(s) - dopamine , chemistry , homovanillic acid , agonist , pharmacology , dopamine receptor , postsynaptic potential , endogenous agonist , haloperidol , amphetamine , medicine , receptor , endocrinology , dopamine receptor d1 , biology , biochemistry , serotonin
Investigation of a novel series of rigid heterocyclic compounds revealed that U‐66444B caused hypothermia in mice which was blocked by haloperidol but not by yohimbine. Inhibition of locomotor activity by U‐66444B was also blocked by haloperidol, and d ‐amphetamine‐stimulated motor activity was antagonized by U‐66444B. These results suggest that this compound might be a dopamine receptor agonist acting at presynaptic receptors to inhibit the release of dopamine. Evaluation of dopamine release by the measurement of 3‐methoxytyramine levels in the corpus striatum revealed that U‐66444B decreased apparent dopamine release. In support of the involvement of presynaptic receptors in the action of this compound, the ability of U‐66444B to reduce the rate of dopamine synthesis (dihydroxyphenylalanine [DOPA] accumulation) was enhanced by gamma butyrolactone and synthesis and metabolism (dihydroxyphenylacetic acid [DOPAC] and homovanillic acid [HVA]) of dopamine in the striatum was not markedly altered by prior kainic acid lesions. Thus, feedback pathways from postsynaptic dopamine receptors did not seem to be principally involved. The measurement of U‐66444B brain levels at various time intervals after s.c. or p.o. administration of the drug to mice revealed that the drug was bioavailable by either route and persisted in brain for up to 2 hr. Studies with the enantiomers of U‐66444B demonstrated that the (+) enantiomer (U‐68553B) was by far the more potent and that this was not related to pharmacokinetics as both enantiomers generated comparable brain levels of drug. U‐68553B appears to be a structurally novel dopamine receptor agonist that has effects at presynaptic dopamine receptors that may be therapeutically useful.