Dopamine receptor stimulating compounds

Hacksell, U. Arvidsson, L.E. Svensson, U. Nilsson, J.L.G. Wikstrom, H. Lindberg, P. Sanchez, D. Hjorth, S. Carlsson, A. Paalzow, L. (1981) Monophenolic 2-(dipropylamino)indans and related compounds central dopamine-receptor stimulating activity. J. Med. Chem. 24, 429-434. 

The enantiomers of the dopaminergic, and orally active 6,7,8,9-te-trahydro-jV,A-dimethyl-3 -benz[e]indol-8-amine (54) were studied for their actions on central dopamine and serotonin (5-HT) receptors [123]. The dopaminergic effects were shown to reside in the (- -)-(/ )-enantiomer. Very interestingly, it was shown that racemic (54) and its (- -)-(i )-enantiomer possess potent central 5-HT 1A receptor stimulating properties, which was not reported originally [124]. Still another indication of the trend in DA agonist SAR towards heterocyclic bioisosteres is given by compound (55) [125]. 

Dopamine receptor agonists. Deficient dopaminergic transmission in the striatum can be compensated by ergot derivatives (bromocriptine p. 114], lisu-ride, cabergoline, and pergolide) and nonergot compounds (ropinirole, prami-pexole). These agonists stimulate dopamine receptors (D2, D3, and D sub-types), have lower clinical efficacy than levodopa, and share its main adverse effects. 

Interestingly, the natural hallucinogens, such as peyote and mescaline (and nearly all other hallucinogens) do not engender compulsive drug seeking or addiction, nor do they lead to chemical dependence. Part of the reason is that these compounds do not stimulate the dopaminergic reward center in the brain, as they lack affinity for the dopamine receptor and the dopamine uptake transporter. 

In addition to the posts)maptic receptors, dopamine autoreceptors also exist on the nerve terminals, dendrites and cell bodies. Experimental studies have shown that stimulation of the autoreceptors in the somatodendritic region of the neuron slows the firing rate of the dopaminergic neuron while stimulation of the autoreceptors on the nerve terminal inhibits both the release and the synthesis of the neurotransmitter. Structurally, the autoreceptor appears to be of the D2 type. While several experimental compounds have been developed that show a high affinity for the autoreceptors, to date there is no convincing evidence for their therapeutic efficacy. 

It is believed that the mechanism of action of amphetamines lies in their ability to release epinephrine (adrenaline) and dopamine from presynaptic nerve endings, which stimulate the corresponding receptors in the CNS. It is also possible that they reduce neuronal uptake of amines as well as inhibit their degradation by monoaminoxidase (MAO). Characteristic of this series of compounds is the effect on the respiratory center, on the satiation center located in the hypothalamus, which leads to suppression of feelings of hunger, thus allowing analog of the examined compounds to be used as anorectics. 

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