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.

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.

Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an additional hydroxyl group into the 4 position of the aromatic ring gives a compound with dopaminergic activity but lacking selectivity for autoreceptors. 3-(3-Hydroxyphenyl)-N-n-propylpyrrolidine, 3-(3-hydroxy)-N-n-propylperhydroazepine, and 3-(3-hydroxyphenyl)quinuclidine were all inactive. The most potent compounds were the N-isopropyl-, N-n-butyl-, N-n-pentyl-, and N-phenethyl-substituted 3-(3-hydroxyphenyl)piperidine derivatives. None of the compounds investigated seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

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A series of 2-(alkylamino)tetralins related to 8-hydroxy-2-(di-n-propylamino)tetralin (21) were prepared and tested as dopamine (DA) and 5-hydroxytryptamine (5-HT) receptor agonists. Several of the compounds were potent 5-HT agonists devoid of DA-mimetic effects. N-Ethyl or N-propyl substitution of 8-hydroxy-2-aminotetralin gave the most potent agonists. It was shown that the most potent compound, (+)-21, has the 2R configuration. 5,8-Di-methoxy-2-(di-n-propylamino)tetralin (31) was found to be a weak DA agonist devoid of 5-HT activity. The corresponding indan derivative, 4,7-dimethoxy-2-(di-n-propylamino)indan (39), has been reported to be active on both DA and 5-HT receptors. The 5-HT-stimulating properties of compounds 21 and 39 as compared to the incapability of compound 31 to activate the 5-HT receptor is tentatively explained by the assumed mode of binding of the compounds to the 5-HT receptor.