8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity

Abstract

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.

Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5‐HT1Aand 5‐HT1Breceptor agonists 8‐OH‐DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD‐299 and NAS‐181

“…Thus, for example, (7)-pindolol can antagonize the 8-OH-DPATinduced facilitation of male rat ejaculatory behaviour (Ahlenius & Larsson, 1988). In addition, (7)-pindolol treatment will enhance the 5-HTP-induced inhibition of male rat ejaculatory behaviour (Ahlenius & Larsson, 1991a;, presumably due to disinhibition of autoreceptor-mediated inhibition of ®ring in serotonergic neurons (see Aghajanian, 1995), as well as in synthesis (Hjorth et al, 1982;Hillegaart et al, 1990) and release (Hutson et al, 1989;Sharp et al, 1989) of forebrain serotonin. In support for this view, the inhibition of male rat ejaculatory behaviour produced by 5-HTP was also enhanced by pretreatment with the 5-HT 1A receptor antagonist WAY-100635 (Ahlenius & Larsson, 1998).…”

“…Anpirtoline (Engel et al, 1989;Swedberg et al, 1992) has been characterized as a 5-HT 1B receptor agonist, whereas isamoltane (Renyi et al, 1991) and NAS-181 (Berg et al, 1998) in particular, represents new 5-HT 1B receptor antagonists. As 5-HT 1A receptor agonist we used the well de®ned prototype agent 8-hydroxy-2-di-npropylamino)tetralin (8-OH-DPAT) (Arvidsson et al, 1981;Hjorth et al, 1982). The availability of these selective tools made the present study possible, where we examined the speci®c roles of brain 5-HT 1A and 5-HT 1B receptor subtypes in the mediation of male rat ejaculatory behaviour.…”

Effects of 8‐OHDPAT and 5‐HT1A antagonists WAY100135 and WAY100635, on guinea‐pig behaviour and dorsal raphe 5‐HT neurone firing

“…The relative selective 5-HTlA agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (Arvidsson et al, 1981;Hjorth et al, 1982) elicits several components of the 5-hydroxytryptamine (serotonin) syndrome such as head weaving, reciprocal forepaw treading and flat body posture in rats (Tricklebank et al, 1984) though the role of 5-HT7 receptors remains to be determined (Lovenberg et al, 1993). Presynaptic 5-HT depletion does not affect the 8-OHDPAT-induced syndrome in either rats or mice (Dourish et al, 1985;Yamada et al, 1988) indicating that the elements of the 5-HT syndrome are mediated via postsynaptic An increase in 5-HT synthesis and hence 5-HT levels (Hess & Doepfner, 1961;Grahame-Smith 1971a;Ortmann et al, 1980) also elicits the syndrome, as do the direct agonists 5-methoxy-N,N-dimethyltryptamine (Grahame-Smith 1971b;Green et al, 1981), 5-methoxytryptamine (Green et al, 1976), (+ )-lysergic acid diethylamide (LSD) (Trulson & Jacobs, 1976a) and quipazine (Green et al, 1976;.…”

Comparison of the effects of IVth ventricular administration of some tryptamine analogues with those of 8‐OH‐DPAT on autonomic outflow in the anaesthetized cat

“…In investigating the function method for investigating the specific role of different receptor of 5-HTIA receptors in cardiovascular regulation the most subtypes in vivo is the use of agonists for that particular commonly used agonist is the aminotetralin 8-hydroxy-2-(disubtype. Although in the case of the 5-HTA receptor subtype n-propylamino)tetralin HBr (8-OH-DPAT) a simplified ergot these agonists are more selective than the available congener (Hjorth et al, 1982). In addition, a small amount of antagonists, they may still not be totally selective and data exists on other agonists, such as flesinoxan, an Nsubstituted phenylpiperazine analogue .…”