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Cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors

An in vivo brain microdialysis study

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Summary

The somatodendritic 5-HT1A autoreceptor regulating 5-HT neuronal activity is currently poorly defined pharmacologically because there are no specific antagonists, but also because potent and stereoselective agonists are scarce. Moreover, there have been few, if any, attempts to specifically investigate structure-activity relationships for agonists acting at this site. Employing brain microdialysis techniques, we have examined the effects of the enantiomers of cis-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (ALK-3; 0.01-0.3 mg/kg s.c.), its trans-1-methyl analogue (ALK-4; 0.3 mg/kg s.c.) and the pure enantiomers of the parent compound - 8-OH-DPAT (0.3 mg/kg s.c.) — in an attempt to address stereochemical agonist structure-activity requirements of 5-HT release-controlling 5-HT1A autoreceptors in brain. The cis-1-methylated 8-OH-DPAT analogue (+)ALK-3 was comparable to the parent compound in reducing the 5-HT output from rat ventral hippocampus. In comparison, both (−)ALK-3 and the racemic rans-diastereomer to ALK-3, ALK-4, were inactive, while the two stereoisomers of 8-OH-DPAT strongly reduced 5-HT release. Pretreatment with (−)pindolol (8 mg/kg s.c.), which has high affinity for 5-HT1A radioligand binding sites, blocked the reduction of hippocampal 5-HT release induced by a submaximally effective dose of (+)ALK-3. The direct intrahippocampal administration of (+)ALK3 (10 μM) via the perfusion medium did not affect 5-HT output.

In summary, the data indicate that (+)ALK-3, like 8-OH-DPAT, is a very potent 5-HT receptor agonist which inhibits terminal 5-HT release in rat hippocampus, probably via activation of somatodendritic 5-HT1A autoreceptors. However, unlike 8-OH-DPAT, (+)ALK-3 is highly stereoselective and may therefore represent a useful probe in the further characterization of 5-HT1A receptor-mediated mechanisms and function. The present study defines some of the stereochemical requirements for 5-HT1A receptor interaction, emphasizing the importance of the receptor region complementary to the C1 and C2 carbons of the 8-OH-DPAT molecule. These findings contribute to the establishment of structure-activity relationships for the cell body 5-HT1A autoreceptors and might be of value in resolving structural features that determine agonist/antagonist activity at central 5-HT1A receptors. Finally, in conjunction with our recent finding that (+)ALK-3 is a partial agonist at postsynaptic 5HT1A receptors, the present study extends previous observations suggesting that pre- and postsynaptic 5-HT1A receptor populations differ in their characteristics.

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Authors and Affiliations

  1. Department of Pharmacology, University of Göteborg, P.O. Box 33 031, S-400 33, Göteborg, Sweden

    Stephan Hjorth

  2. MRC Unit and University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, OX2 6HE, Oxford, England

    Stephan Hjorth & Trevor Sharp

  3. Department of Organic Pharmaceutical Chemistry, University of Uppsala Biomedical Center, Uppsala, Sweden

    Ye Liu

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Hjorth, S., Sharp, T. & Liu, Y. Cis-(+)-8-OH-1-CH3-DPAT, (+)ALK-3, a novel stereoselective pharmacological probe for characterizing 5-HT release-controlling 5-HT1A autoreceptors. Naunyn-Schmiedeberg's Arch Pharmacol 341, 149–157 (1990). https://doi.org/10.1007/BF00169724

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