SummaryIt was demonstrated that the simplified ergot congener 8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, is able to elicit pronounced biochemical and behavioural alterations indicative of central serotoninomimetic activity. Since these effects are resistant to prior monoamine depletion and/or synthesis inhibition by means of reserpine and a-propyldopacetamide (H22/54), respectively, they are most likely to be attributable to direct serotonin-receptor agonism by 8-OH-DPAT. With regard to central 5-HT neurotransmission the effects of 8-OH-DPAT-increased 5-HT levels, decreased 5-HIAA levels, 5-HT-synthesis rate and 5-HT utilization and inhibited 5-HT neuronal firing--are virtually identical, and comparable in potency, to those reported to result from the administration of lisuride or LSD. In contrast, however, to lisuride and LSD (included for comparative purposes in this study) as well as to several differently N-substituted, 5,6-dihydroxy, 6,7-dihydroxy and 5-,6-and 7-monohydroxy 2-aminotetralins, 8-OH-DPAT lacks appreciable effects on * Presented in part at the 19th ACNP meeting, San Juan, December 15-19,1980. [Psychoph. Bull. 17, 180-183 (1981 central catecholamine receptors. The compound may thus be regarded tho most potent, selective centrally acting 5-HT agonist described to date. accordance with this it was shown that the full-blown 5-HT-like behaviou: syndrome induced by 8-OH-DPAT cannot be antagonized by reserpir. phenoxybenzamine, propranolol and haloperidol. In addition, of the thl putative 5-HT-receptor blockers cyproheptadine, methergoline and methl thepin only the latter was able to counteract the 8-OH-DPAT-induc~ syndrome. The results are discussed in relation to the recent subclassific tion of central 5-HT receptor sites.A comparison between the chemical structures and biological activiti for different fragments of the ergot nucleus was also made. The data sugg~ that while the role of the A ring in the ergot structure for dopaminer activity at present is unclear, this ring may be important for the 5-t activity like in e.g. lisuride and LSD.Moreover, based on the present results and literature reports, it is spe, lated that a selective 5-HT-receptor agonist such as 8-OH-DPAT would i be liable to induce hallucinations in man.

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Communications to the Editor 8-Hydroxy-2-(di-n-propylamino)tetralin, a New Centrally Acting 5-Hydroxytryptamine Receptor Agonist Sir:We are currently investigating the pharmacological properties of 2-aminotetralins and related compounds using biochemical and behavioral methods recently published.1,2 It has been previously shown that 5-hydroxy-(1), 6-hydroxy-(2) and 7-hydroxy-2-(di-n-propylamino)tetralin (3) exhibit considerable dopamine (DA) receptor stimulating activity.3,4 In this series, the 5-hydroxy isomer 1 is the most active compound, being a highly active central DA-receptor agonist. Now we report the pharmacological properties of 8hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 4) which are consistent with the characterization of this compound as a central 5-hydroxytryptamine (5-HT) receptor agonist, devoid of DA-receptor stimulating activity. The DA-receptor-active 2-aminotetralins (1-3) are included for comparative purposes in this study. We are also presenting the resolution of 4 and the testing results for the enantiomers.

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The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.

A detailed structure-activity relationship is revealed for resolved, centrally acting dopamine (DA) agonists acting on both pre- and postsynaptic DA receptors. The compounds resolved are 5- and 7-hydroxy-2-(di-n-propylamino)tetralin and cis- and trans-7-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline. By the superimposition of the structures of the more active enantiomers of these compounds with those of known dopaminergic agonists, apomorphine and ergolines, a new DA-receptor model is proposed as an outgrowth of current DA-receptor theories. One of the most important concepts of this receptor model is its emphasis on the possible positions taken by the N-substituents of dopaminergic compounds. One of these positions i sterically well defined while the other direction is sterically less critical. The model has been used to explain the lack of dopaminergic activity of some previously reported structures and also to predict properties of novel structures, including inherent chirality, which should be active at DA receptors. Hopefully, this heuristic DA-receptor model will lead to the discovery of more selective and potent pharmacological tools, which ultimately might lead to the development of therapeutic agents for treating diseases of dopaminergic function in the central nervous system.

In recent years, it has been suggested that oxidative stress is a feature of Alzheimer's disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro-oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro-oxidant, while melatonin exerts an antioxidant action in Al-treated animals. The protective effects of melatonin against cellular damage caused by Al-induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.