Uses of dopamine receptor agonists

Selective dopamine D1 receptor agonists for use in the treatment of primary degenerative dementia, depression, anxiety, obesity or schizophrenia.

The present invention relates to new uses of dopamine receptor agonists. 
More particularly the present invention relates to the use of selective 
dopamine D1 receptor agonists for the treatment of primary degenerative 
dementia, e.g. senile dementia, particularly of the Alzheimer type. 
Selective dopamine D1 receptor agonists are drugs producing therapeutic 
actions which are predominantly mediated by dopamine receptors of the D1 
type (D1 receptors). D1 receptors are defined on the widely accepted 
classification originally based on biochemical criteria, disclosed by 
Kebabian and Calne in Nature, 277: 93-96 (1979). 
Senile dementia, particularly senile dementia of the Alzheimer type (SDAT), 
is one of the most common causes of metal deterioration in the elderly. 
This brain disease produces a progressive deterioration of cognitive 
functions, affect and behaviour, leading to the clinical syndrome of 
dementia. 
SDATT is characterized neuropathologically by the presence of widespread 
senile plaques and neurofibrillary tangles in the cerebral cortex and in 
limbic structures, particularly the hippocampal formation. 
Neurochamically, a marked loss of presynaptic cholinergic markers in the 
cortex and hippocampus has been observed in SDAT brains. Besides the 
cholinergic deficit, many other neurochemical changes have been reported 
in the brains of SDAT patients. However dopamine receptors have not been 
extensively studied in SDAT. 
In accordance with the present invention it has now surprisingly been found 
that in SDAT patients D1 receiptor densities were markedly and selectively 
decreased in the hippocampus. 
As compared to controls, the decrease of D1 binding in the SDAT hippocampus 
represented the 89 % in the dentate gyrus (2P&lt;0.022), the 74 % in the CA3 
(2P&lt;0.007), and the 57 % in the CA1 (2P &lt;0.007). 
The decrease of D1 receptor densities has been found using quantitative 
autoradiography and newly developed selective ligands for D1 and D2 
receptors and examining in detail the distribution of D1 and D2 receptors 
in the control human brain and the alterations in the density and 
localization of these receptors in SDAT patients. The dopaine antagonist 
[.sup.3 H]SCH 23390 [Iorio et al., J. Pharmacol. Exp. Ther., 226 (1983), 
462-468]has been used as a ligand. 
Brains were obtained at autopsy from 15 subjects with no known hitory of 
neurologic or psychiatric disease (8 male and 7 female; mean age 65.+-.3 
years; mean postmortem delay 10.7.+-.h) and 7 patients witha diagnosis of 
SDAT (2 male and 5 female; mean age 84.+-.2 years; postmortem delay 12.9 
.+-.2 h) were included in this study. SDAT was confirmed 
histopathologically by the presence of senile plaques in high numbers and 
neurofibrillary tangles in the cortex and hippocampus. Brains were 
promptly removed at autopsy and dissected. Tissue blocks were frozen and 
kept at -20.degree.C. Slide-mounted microtome section (10 .mu.m thick) 
were inubated for 45 minutes at room tempeature with 1 nM [.sup.3 H]SCH 
23390 in 50 mM Tris HC1 containing 120 mM NaC1, 5 mM KC1, mM CaC1.sub.2 
and MgC1.sub.2, pH 7.4, washed for 5 minutes in fresh cold buffer and 
rapidly dried under a stream of cold air. Blanks were obtained by 
coincubation with 10.sup.-6 cis-flupentixol. To generate autoradiograms 
the incubated tissues were exposed to [.sup.3 H]Ultrofilm (LKB, Sweden), 
together with [.sup.3 H]standards. Films were analyzed by 
microdensitometry using a computerized image-analysis sytem. 
The above findings indicate that selective dopamine D1 receptors agonists 
are useful for the treatment of SDAT and more generally for the treatment 
of primary degenerative dementia, e.g. senile dementia. 
The selective dopamine D1 receptor agonists for use in accordance with the 
invention include e.g. the compound known in the literature under the code 
name SKF 38393 (Setler et al.,. European J. Pharmacol. 50, 419 -430, 1978) 
or an indolophenanthridine of formula I 
##STR1## 
wherein R.sub.1 and R.sub.3 independently are hydrogen, (C.sub.1-4)alkyl, 
(C.sub.3-5)alkenyl wherein the double bond is not adjacentn to the 
nitrogen atom, (C.sub.3-6)cycloalkyl(C.sub.1-3)alkyl, 
phenyl(C.sub.1-3)alkyl optionally substituted in the phenyl ring by 
(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, hydroxy or halogen, or 2- or 
3-furyl(C.sub.1-3)alkyl, 
R.sub.2 is hydrogen, chlorine, bromine or methyl, 
X.sub.1 and X.sub.2 independently are hydrogen, (C.sub.1-4)alkyl, 
(C.sub.1-4)alkooxy, hydroxy, halogen or trifluoromethyl, 
in free base or pharmaceutically acceptable acid addition salt form. 
The compounds of formula I and their pharmaceutically acceptable acid 
addition salts as well as a process for their production are known e.g. 
from U.S. Pat. No. 4,634,708. This patient also discloses the use of the 
compounds as dopamine receptor stimulants, e.g. both in the treatment of 
congestive cardiac insufficiency and of hypertension, or of renal failure 
with reduced urine excretion, as selective dopaminergic active agents, 
e.g. for the treatment of Parkinson's disease, and as analgesic agents, 
e.g. in the treatment of pain. 
The utility according to the inventtion of selective dopamine D1 receptor 
agonists was confirmed in clinical trials with healthy volunteers and 
patients suffering from clinically diagnosed SDAT. The reactios of the 
patients suffering from SDAT in cognition and vigilance tests were 
compared with those of control groups. With the 
(-)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridi 
ne, 7-methylindolo [4,3 ab ]phenanthrideine, for example, significant 
improvements in cognitive functions such as orientation and memory could 
be achieved after repeated oral administration of up to 30 mg/day during 
approx. 10 weeks. The compound was well tolerated by the patients and the 
healthy volunteers. 
The selective dopamine D1 receptor agonists are therefore useful for the 
treatment of primary degenerative dementia, e.g. senile dementia, 
particularly SDAT. 
The present invention accordingly provides a selective dopamine D1 receptor 
agonist for use in the treatment of primary degenerative dementia, e.g. 
senile dementia, particularly SDAT. 
The present invention further provides a method of treating primary 
degenerative dementia, e.g. senile dementia, particularly SDAT, which 
comprises administering to a subject in need of osuch treatment a 
selective dopamine D1 receptor agonist. The invention also provides a 
pharmaceutical composition comprising a selective dopamine D1 receptor 
agonist, for use in the treatment of prmary degenerative dementia, e.g. 
senile dementia, particularly SDAT. Such compositions may be formulated in 
conventional malnner, so as to be for example a solution or a tablet. 
In accordance with the present invention it has furthermore surprisingly 
been found that selective dopamine D1 receptor agonists are useful as 
antidepressants, anxiolytics and anti-obesity agents. 
The selective dopamine D1 receptor agonists of formula I and their 
pharmaceutically acceptable acid addition salts have been found to be 
particularly suitable for said uses. 
The utility of selective dopamine D1 receptor agonists as anti-depressants 
is indicated by animal tests, e.g. by the inhibition of 
tetrabenazine-induced catalepsy and ptosis in the rat. Groups of 6 rats of 
a Sprague-Dawley derivation receive the test substance 30 minutes before 
tetrabenazine (10 mg/kg i.p.). 40 Minutes after tetrabenazine the 
catalepsy of each rat is estimated by placing the forepaws on a 7 cm high 
wooden block. The time for which the animal remain in this unnatural 
position is measured, up to a maximum of 45 seconds. Immediately after 
determining the catalepsy, the degree of ptosis is scored on a 4-point 
scale. No ptosis is represented by 1 whereas a score of 4 indicates 
complete eye-closure. The values from the separately scored eyes are 
added, so that the maximum score possible is 8. If a catalepsy of 29 
seconds or less is observed, the tetrabenazine-induced catalepsy is said 
to be antagonised. Rats with a ptosis score of less than 3 are said to be 
protected against the ptotic effect of tetrabenazine. This procedure is 
repeated 60 minutes after tetrabenazine. The antagonistic effects are 
expressed as percentages. 
In the above test selective dopamine D1 receptor agonists inhibit the 
tetrabenazine-induced catalepsy and ptosis upon administering doses of 5 
to 50 mg/kg i.p. For example with the 
(-)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylindolo[4,3-ab]phenanthridi 
ne, a 100% inhibition of the catalepsy and a 33% inhibition of the ptosis 
were observed at a dose of 30 mg/kg i.p. 
Selective dopamine D1 receptor agonists also show activity in the 
behavioral despair test [R. D. Porsolt et al., Arch. Int. Pharmacodyn., 
229, 327-336 (1977)]upon administering does of 10 to 100 mg/kg p.o. With 
the above mentioned compound, for example, a dose of 30 mg/kg p.o. 
resulted in an almost 50 % reduction of immobility time in two separate 
experiments. 
Selective dopamine D1 receptor agonists are therefore useful as 
antidepressants. 
The present invention accordingly provides a selective dopamine D1 receptor 
agonist, preferably a compound of formula I in free base form or in 
pharmaceutically acceptable acid addition salt form, for use as an 
antidepressant.

The present invention further provides a method of treating depression, 
which comprises administering to a subject in need of such treatment a 
selective dopamine D1 receptor agonist, preferably a compound of formula I 
or a pharmaceutically acceptable acid addition salt thereof. The acid 
addition salt forms exhibit the same order of activity as the free bases. 
The invention also provides a pharmaceutical composition comprising a 
selective dopamine D1 receptor agonist, preferably a compound of formula I 
in free base form or in pharmaceutically acceptable acid addition form, 
for use in the treatment of depressions. Such compositions may be 
formulated in conventional manner, so as to be for example a solution or a 
tablet. 
The utility of selective dopamine D1 receptor agonists as anxiolytics is 
indicated by animal tests, e.g. by the four plates test according to C. 
Aron et al., Neuropharmacology 10, 459 - 469 (1971). In this test the 
selective dopamine D1 receptor agonists show activity upon administering 
doses of 10 to 100 mg/kg p.o. The 
(-)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanthrid 
ine, for example, significantly prevents the inhibition of the exploratory 
behaviour at a dose of 30 mg/kg p.o. 
Selective dopamine D1 receptor agonists are therefore useful as 
anxiolytics. 
The present invention accordingly provides a selective dopamine D1 receptor 
agonist, preferably a compound of formula I in free base form or in 
pharmaceutically acceptable acid addition salt form, for use as an 
anxiolytic. 
The present invention further provides a method of treating anxiety, which 
comprises administering to a subject in need of such treatment a selective 
dopamine D1 receptor agonist, preferably a compound of formula I or a 
pharmaceutically acceptable acid addition salt thereof. The acid addition 
salt forms exhibit the same orer of activity as the free bases. The 
invention also provides a pharmaceutical composition comprising a 
selective dopamine D1 receptor agonist, preferably a compound of formula I 
in free base or in pharmaceutically acceptable acid addition form, for use 
in the treatment of anxiety. Such compositions may be formulated in 
conventional manner, so as to be for example a solution or a tablet. 
The utility of selective dopamine D1 receptor agonists as antiobesity 
agents is indicated by animal tests, e.g. by their ability to decrease 
body weight and food consumption in the dog upon administering doses of 7 
to 28 mg/kg/day, or their activity in the Competitive Feeding Situation 
Test. 
In this test, pairs of male OF-1 mice are forced to compete over 10 minutes 
for a single food pellet by depriving them of food for 6 hours prior to 
placing both mice in a neutral cage. Because of the close proximity 
between the mice, the tendency to eat is competitively offset by the 
tendency to interact socially. One partner receives the drug and the other 
receives the placebo by the oral route, 1 hour before testing. Frequencies 
and durations of social activities and eating bouts are records for both 
animals. Drug effects are determined by calculating the mean differences 
between the behavioural responses of drugged and placebo-treated partners 
(within groups). In all cases 8 pairs of mice/treatment are tested, the 
Wilcoxon sign rank test being used to judge significances of effects 
within groups (p&lt;0.05, 2-tailed). A separate group in which both partners 
receive the vehicle serves as an independent control. Differences between 
the scores of these mice and the test groups are judged using the 
Mann-Whitney U test (i.e. across group comparisons). 
In the above test selective dopamine D1 receptor agonists induced a 
dose-dependent reduction of eating upon administering doses of 3 too 30 
mg/kg p.o., whereas at the same dosages the number of social interactions 
did not change significantly. For example with the 
(-)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3-ab]phenanthrid 
ine, a dose of 10 mg/kg p.o. resulted in a decrease of 43% in frequency and 
of 85 % in duration of the eating bouts. 
Selective dopamine D1 receptor agonists are therefore useful as 
anti-obesity agents. 
The present invention accordingly provides a selective dopamine D1 receptor 
agonist, preferably a compound of formula I in free base form or in 
pharmaceutically acceptable acid addition salt form, for use an an 
anti-obesity agent. 
The present invention further provides a method of treating obesity, which 
comprises administering to a subject in need of such treatment a selective 
dopamine D1 receptor agonist, preferably a compound of formula I or a 
pharmaceutically acceptable acid addition salt thereof. The acid addition 
salt forms exhibit the same order of activity as the free bases. The 
invention also provides a pharmaceutical composition comprising a 
selective dopamine receptor agonist, preferably a compound of formula I in 
free base or in pharmaceutically acceptable acid addition form, for use in 
the treatment of obesity. Such compositions may be formulated in 
conventional manner, so as to be for example a solution or a tablet. 
The various indications mentioned above suggest that selective dopamine D1 
receptor agonists are also useful in schizophrenics. 
The present invention accordingly provides a selective dopamine D1 receptor 
agonist, preferably a compound of formula I in free base for or in 
pharmaceutically acceptable acid addition salt form, for use in the 
treatment of schizophrenia. 
The present invention further provides a method of treating schizophrenia, 
which comprises administering to a subject in need of such treatment a 
selective dopamine D1 receptor agonist, preferably a compound of formula I 
or a pharmaceutically acceptable acid addition salt thereof. The acid 
addition salt forms exhibit the same order of activity as the free bases. 
The invention also provides a pharmaceutical composition comprising a 
selective dopamine D1 receptor agonist, preferably a compound of formula I 
in free base or in pharmaceutically acceptable acid addition form, for use 
in the treatment of schizophrenia. Such compositions may be formulated in 
conventional manner, so as to be for example a solution or a tablet. 
For all above mentioned indications, the appropriate dosage will of course 
vary depending upon, for example, the compound employed, the host, the 
mode of administration and the nature and severity of the condition being 
treated. However, in general, satisfactory results are indicated to be 
obtained at daily dosages from about 1 to 100 mg/kg animal body weight. In 
larger mammals, for example humans, an indicated daily dosage is in the 
range from about 20 mg to about 200 mg. 
The compounds for use according to the invention may be administered by any 
conventional route, in particular enterally, preferably orally, e.g. in 
the form of tablets or capsules, or parenterally, e.g. in the form of 
injectable solutions or suspensions. 
Suitable dosage forms, e.g. for oral administration, contain from about 5 
to 100 mg of a compound for use according to the invention, together with 
a pharmaceutically acceptable diluent or carrier therefor. 
The present invention moreover provides the use of a selective dopamine D1 
receptor agonist for the manufacture of a pharmaceutical composition for 
treating primary degenerative dementia, depression, anxiety, obesity or 
schizophrenia. 
The preferred selective dopamine D1 receptor agonist for use according to 
the invention is the 
(-)-(6aR,12bR)-4,6,6a,7,8,12b-hexahydro-7-methylidolo[4,3-ab]phenanthridin 
e. The preferred indication is SDAT. 
Gelatine capsules having the following composition may be prepared 
according to conventional methods and are suitable for use in the 
treatment of primary degenerative dementia, e.g. SDAT, depression, 
anxiety, obesity or schizophrenia: 
______________________________________ 
Compound of formula I, e.g. 
(-)-trans-4,6,6a,7,8,12b-hexahydro-7-methyl- 
indolo[4,3-ab]phenanthridine in free base form 
10 mg 
Lactose 165.5 mg 
Silicium dioxide (Aerosil 200) 
1.5 mg 
Corn Starch 120 mg 
Magnesium stearate 3 mg 
total 300.0 mg 
empty capsule 77.0 mg 
final weight 377.0 mg 
______________________________________