It is well established that compounds which interact with central dopamine receptors have therapeutic potential in the treatment of conditions like Parkinson's disease and psychotic disorders. For the later treatment, it is known that tardive dyskinesia (TD) is a major limitation of chronic antipsychotic drug therapy at least with older (typical) antipsychotics.
There is increased awareness of the different ways in which this condition manifests itself and the variety of disabilities that TD produces. Although a substantial research has been stimulated to identify the underlying pathophysiological mechanisms of TD, they remain largely elusive. There are several hypotheses about the pathophysiology of TD (dopamine hypersensitivity, neurotoxicity, GABA insufficiency, noradrenergic dysfunction, structural abnormalities)[1
], however the true mechanism remains unknown.
The hypothesis of dopamine hypersensitivity proposes that the nigrostriatal dopamine system develops increased sensitivity to dopamine as a consequence of chronic dopamine receptor blockade induced by neuroleptic drugs. There is an increased incidence and prevalence of involuntary hyperkinetic dyskinesia in patients receiving dopamine antagonists in most [1
] but not all reports [4
]. Dopamine antagonists usually suppress TD, whereas dopamine agonists aggravate TD symptoms [6
An alternate, though highly speculative hypothesis, is the proposal that TD is due to neurotoxic effects induced by free radical byproducts from catecholamine metabolism. The basal ganglia, by virtue of their high oxidative metabolism, are vulnerable to membrane lipid peroxidation as a result of the increased catecholamine turnover induced by neuroleptic drugs [7
]. It is known that vitamin E (a-tocopherol) serves as a free radical scavenger, thus reducing the cytotoxic effects of free radicals. Clinical studies have produced conflicting data in this area. The impression gained from these studies was that while vitamin E is safe and well-tolerated, it confers only modest benefits. Some studies do not support the hypothesis that TD is mediated through free radical damage to neurons [8
] while others support that vitamin E appears to be effective in reducing the severity of TD, especially in patients who are young and have recently developed TD [12
Early neuroleptic agents showed great antipsychotic promise initially, however, the induction of extrapyramidal side effects associated with their use constituted a significant problem. Atypical antipsychotics possess a lower extrapyramidal side effects liability and show a better efficacy in the treatment of negative and depressive symptoms as well as cognitive disorders associated with schizophrenia. These features have been related to a higher affinity to serotonin receptors. However, they brought about various side effects such as weight gain, hyperglycemia, cholesterol level elevation, and QT interval prolongation [14
A novel antipsychotic agent with a mechanism of action different from all currently marketed typical and atypical antipsychotics is aripiprazole. This quinoline derivative exerts potent partial agonistic action on D2
receptors and antagonistic properties at 5-HT2A
receptors. Aripiprazole claims to be the first agent of a third generation of antipsychotics, the so-called "dopamine-serotonin stabilizers"[14
In a previous study [15
] we have shown that 6,7,8,9-tetrahydro-N,N,-di-n-propyl-1H
-benz [g]indole-7-amine (PBIA
) (Figure ) acts in vivo
as a functional dopamine receptor partial agonist. It is known that a partial agonist at any dose level can not produce the same maximal biological response as a full agonist even though the partial agonist binds as tightly and as well to the receptor as the full agonist. In sum, a partial agonist has high affinity for its receptor, but low intrinsic activity. PBIA
is a moderate [3
H]-spiperone and 8-OH-[3
H]-DPAT competitor. Spiperone is a selective D2
antagonist while 8-OH-DPAT is a selective 5-HT1A
agonist. This means that PBIA
expresses a moderate binding affinity at the dopamine D2
and serotonin 5-HT1A
receptors in in vitro
competition binding assays.
Structure of 6,7,8,9-tetrahydro-N,N,-di-n-propyl-1H-benz [g]indole-7-amine (PBIA), 1-p-toluenesulfonyl-6,7,8,9-tetrhydro-N,N-di-n-propyl-1H-benz [g]indol-7-amine (TPBIA) and 5-OH-DPAT
PBIA was designed as a metabolically stable bioisostere of the potent dopamine receptor agonist 5-OH-DPAT, (Figure ). Phenolic dopamine receptor agonists suffer from poor bioavailability due to rapid metabolic inactivation via conjugation. Thus, an approach which has been pursued to overcome this problem is to develop non phenolic heterocyclic analogues. In this respect, evidence indicates that an indole NH moiety can be a bioisostere of the hydrogen-bonding H donor properties of the phenolic OH group in dopamine agonists. Based on the above, we synthesized PBIA.
In the present work, we tested the derivative 2
(Figure ), 1-p-toluenesulfonyl-6,7,8,9-tetrhydro-N,N-di-n-propyl-1H
-benz [g]indol-7-amine (TPBIA
) for behavioral effects in rats, related to interactions with central dopamine receptors. Because TPBIA
has an increased lipophilicity and an appropriate polar molecular surface area (PSA) value, we hypothesized that it might be capable of penetrating the blood-brain barrier in a considerable degree. Additionally, the presence of the tosyl group might shift the agonistic activity to that of an antagonist. It is documented that increasing the van der Waals molecular volume of an agonist makes it an antagonist [16
]. Finally, since free radical and oxidative stress may be implicated in the pathophysiology of a number of neurodegenerative diseases [17
] we also investigated the antioxidant potential of TPBIA
, since there are some reports concerning the role of free radicals in TD [7
Therefore, it becomes interesting to design compounds that maintain antipsychotic efficacy and simultaneously could be free of TD risk.
The aim of the current study was:
1) to find if TPBIA crosses the blood-brain barrier,
2) to test the behavioral effects of TPBIA with specific focus on neuroleptic effects,
3) to test its antioxidant activity.