2-hydroxy-apomorphine

H]spiperone binding test) and in vivo (catalepsy induction, and antagonism of apomorphine-induced stereotypy in rats antagonism of apomorphine-induced emesis in dogs). On the other hand, antagonism of cisplatin-induced emesis in the dog and ferret was retained. Several representative /J-keto, ji-hydroxy and / -methoxy analogues are shown in Table 7.1. 

The importance of resolution and determination of absolute configuration cannot be overemphasized. There was, in this writer s opinion, little significant progress in developing useful receptor models prior to the determination of the absolute configurations for the active enantiomers of apomorphine, I, certain N-substituted 5-hydroxy-2-amino-l,2,3,4-tetrahydronaphthalenes, and of 6,7-ADTN (X). It is very common to see structures drawn in the literature with their chiral center shown as a particular absolute configuration, for example similar to that of apomorphine. Yet, in many of these cases there is no evidence as to which isomer is active. The reversed stereochemistry for the active enantiomers of apomorphine and... 

Chart 1.4 Chemical structures of dopamine (1), apomorphine (11) and 11-hydroxy-N- -propylnoraporphine (12). 

The drugs were dissolved in degassed ultra pure water with approximately 0.5 mg/ml ascorbic acid to prevent oxidation of the compounds and stocked in a concentration of 300 nmol/ml for subcutaneous administration and 10 pmol/2 ml for oral administration and diluted, if necessary, with degassed ultra pure water before administration. To dissolve R-(-)-ll-hydroxy-aporphine a drop of glacial acetic acid was added. Drugs used were R-(-)-apomorphine.HCl (11), R-(-)-ll-hydroxyaporphine (79), R-(-)-N- -... 

The dose-response relationships of the test compounds are given in Figure 5.2. The response of the compounds is given as the AUC. To compare the AUCs, the experiments were stopped after 180 min. The rank order in the potency upon s.c. administration of the compounds is R-(-)-N-//-propylnorapomorphine (80) > R-(-)- l 1 -hydroxy-N-//-propylnoraporphine (12) > R-(-)-apomorphine (11). 

The relative oral bioavailabilities of R-(-)-apomorphine (11) and two of its analogues 80 and 12 can be found from Figures 5.3A-C. The relative oral bioavailability was determined by comparing the curves and the AUC after s.c. and p.o. administration. When the AUCs were not significantly different, the relative oral bioavailability was determined by dividing the s.c. dose by the p.o. dose and multiplying by 100. It was known that R-(-)-apomorphine (11) possessed a low oral bioavailability. It was expected that the oral bioavailability of the three compounds would be between 1 % and 10 %. Based on this assumption the oral doses were chosen. With this method, both the catechols R-(-)-apomorphine (11) and R-(-)-N- -propylnorapomorphine (80) possess a relative oral bioavailability of about 1 %. The mono-hydroxy compound R-(-)-l l-hydroxy-N- -propylnoraporphine (12) possesses a relative oral bioavailability of about 3%. 

Beside comparable effects on the release of dopamine in the striatum, R-(-)-N- -propylnorapomorphine (80) and R-(-)-l 1-hydroxy-N-n-propylnoraporphine (12) could also possess the same neuroprotective effects as R-(-)-apomorphine. This neuroprotective effect resides in the phenolic moiety, which can act as a radical scavenger.141 143 Both compounds possess this moiety. 

The oxidation of aporphines containing phenolic hydroxy-groups has been studied. The mode of oxidation of apomorphine has been shown to be dependent... 

Of the drugs used to treat Parkinson s disease, only apomorphine and its derivatives, and levodopa (L-DOPA, 3-hydroxy-L-tyrosine), carbidopa (Figure 6.34), and their derivatives and metabolites have been measured by HPLC-ED. 

Hydroxyaporphine can lower the blood pressure of cats. On the other hand, 8-hydroxy-A -w-propylnoraporphine shows no dopamine agonist activity. In fact, the C-10,11 diphenolic system does not seem to be a requirement for dopaminergic activity since 10-hydroxy- and 11-hydroxy-A - -propylnorapor-phine show appreciable activity in rats. j -Ethyl and iV- -propylnorapomor-phine are potent emetics in dogs. The hypotensive effect of apomorphine in the anesthetized cat was also observed with iV- -propylnorapomorphine. ... 

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