Lars-Erik Arvidsson

8-Hydroxy-2-(Di-n-Propylamino)Tetralin, 8-OH-DPAT, a Potent and Selective Simplified Ergot Congener with Central 5-HT-Receptor Stimulating Activity*

It 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 andα-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 central catecholamine receptors. The compound may thus be regarded the most potent, selective centrally acting 5-HT agonist described to date. accordance with this it was shown that the full-blown 5-HT-like behaviour syndrome induced by 8-OH-DPAT cannot be antagonized by reserpin phenoxybenzamine, propranolol and haloperidol. In addition, of the truputative 5-HT-receptor blockers cyproheptadine, methergoline and methrothepin only the latter was able to counteract the 8-OH-DPAT-induce syndrome. The results are discussed in relation to the recent subclassification of central 5-HT receptor sites. A comparison between the chemical structures and biological activities for different fragments of the ergot nucleus was also made. The data suggest, in 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-HT-receptor activity like in e.g. lisuride and LSD. Moreover, based on the present results and literature reports, it is speculated that a selective 5-HT-receptor agonist such as 8-OH-DPAT would be liable to induce hallucinations in man.

Effects of a new type of 5-HT receptor agonist on male rat sexual behavior

8-Methoxy-2-(di-n-propylamino) tetralin (8-OMe-DPAT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) are two new drugs exerting selective actions on brain 5-HT neurotransmission. In the present experiments we have investigated the effects of these two drugs on male rat sexual behavior. It was found that both drugs reduce the number of intromissions preceding ejaculation and shorten the ejaculation latency. These effects are extremely pronounced and several animals ejaculate at the first intromission. In addition 8-OH-DPAT produced a slight reduction of the post-ejaculatory interval. There were no significant effects on latency to initiate copulation or in the number of mounts preceding ejaculation. Finally, sexual behavior was partly or completely restored in castrated male rats after injection with 8-OMe-DPAT or 8-OH-DPAT.

Central dopamine receptor agonist and antagonist actions of the enantiomers of 3-PPP

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.

(+)-UH 232 and (+)-UH 242: novel stereoselective dopamine receptor antagonists with preferential action on autoreceptors.

The (+)- and (−)-enantiomers of the 2-aminotetralin derivatives cis-5-methoxy-1-methyl-2-(di-n-propylamino)tetralin (UH 232) and cis-5-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (UH 242), were pharmacologically evaluated in rats in an extensive series ofin vivo biochemical and behavioral experiments. These studies showed that the (+)- and (−)-enantiomers have differential effects on central dopamine (DA) receptors. Thus, (−)-UH 242 is a DA-receptor agonist stimulating both pre- and postsynaptic receptors. (−)-UH 232 is also active as a DA receptor agonist, although with much lower potency than (−)-UH 242. In contrast, (+)-UH 242 and (+)-UH 232 are characterized as DA receptor antagonists. Both (+)-forms markedly accelerated DA synthesis and turnover and reversed the biochemical and behavioral effects of apomorphine. Locomotor activity was stimulated by the (+)-enantiomers over a wide dose range; hypomotility was induced only by high doses. The pharmacological profile of the (+)-enantiomers clearly differs from that of classical neuroleptics and suggests a preferential antagonistic action on DA autoreceptors. (+)-UH 232 and (+)-UH 242 may prove useful as experimental tools and as potential therapeutic agents (selectively increasing DA-ergic neurotransmission),e.g. in geriatric practice.

Effects of stereoselective 5-HT1A agonists on male rat sexual behavior

The effects on male rat sexual behavior of some new stereoselective 5-HT agonists, related to 8-OH-DPAT, are presented. It was found that (+)cis-8-hydroxy-1-methyl-2-(di-n-propylamino) tetralin (8-OH-MeDPAT), as well as (-)trans-2-(2-hydroxyphenyl)-N,N-di-n-propylcyclopropylamine (2-OH-DCPA), and its 3-hydroxy-phenyl analog (3-OH-DCPA), stereoselectively facilitated the male rat sexual behavior, as evidenced by a decrease in the number of intromissions preceding ejaculation, and a shortening of the ejaculation latency. For the former two compounds, studied in further detail, the potency and efficacy appear to be of the same magnitude as previously found for 8-OH-DPAT. The results demonstrate specific 5-HT receptor involvement in the mediation of male rat sexual behavior.

A homologous series of N-alkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins: central dopamine receptor antagonists showing profiles ranging from classical antagonism to selectivity for autoreceptors.

N-alkylated and N, N-dialkylated cis-(+)-(1 S, 2 R)-5-methoxy-1-methyl-2-aminotetralins were tested for central dopamine receptor antagonism usingin vivo biochemical and behavioral models in rats. The di-methyl analogue showed a profile similar to classical dopamine receptor antagonists. It produced a marked hypomotility including catalepsy and a pronounced increase in dopamine synthesis rate. This compound also displaced DiPr-5, 6-ADTN from striatal binding sites and antagonized the hyperactivity induced by the ligand. In contrast, the mono-propyl analogue increased locomotor activity and dopamine synthesis rate over a wide dose range. This compound failed to antagonize the hyperactivity induced by DiPr-5, 6-ADTN and to displace thisin-vivo binding ligand. Thus, the mono-propyl analogue appears to lack postsynaptic dopamine receptor antagonistic properties; it seems to produce its effects via a selective dopamine autoreceptor antagonism. The di-ethyl and di-propyl, but not the dibutyl, analogues were also active in the models used. Whereas the di-ethyl compound shows a profile similar to classical dopamine receptor blockers, the di-propyl compound appears to act preferentially on autoreceptors.

Recent advances in central 5-hydroxytryptamine receptor agonists and antagonists

Vigorous research efforts during the last fifteen years have led to important advances in the pharmacology and medicinal chemistry of 5-hydroxytryptamine (5-HT, serotonin) and related agents. Progress includes the development of powerful testing methods (such as ligand binding) and the introduction of agents with selective pharmacological actions (such as ketanserin). Several recent reviews have covered selected aspects of the 5-HT literature (see e.g. [1–11]).

Phenolic derivatives of 1,2-methano-N,N-dipropyl-1,2,3,4-tetrahydronaphth-2-ylamine. Structural hybrids of 2-aminotetralin-and phenylcyclopropylamine-derived 5-HT1A-receptor agonists

Abstract Three phenolic derivatives of 1,2-methano- N,N -dipropyl- 1,2,3,4-tetrahydronaphth-2-ylamine 6–8 were synthesized as structural hybrids of the potent 5-HT 1A -receptor agonist 8-OH-DPAT 1 and 2 related phenolic phenylcyclopropylamine 4 and 5 . The new compounds were assayed for 5-HT 1A -receptor affinity and efficacy in vitro . Hybrids 6 and 7 were considered to be inactive but 8 had a K i value of 130 nM for [ 3 H]-8-OH-DPAT labelled 5-HT 1A -receptors and produced an inhibition of the cAMP-production in the VIP-stimulated adenylyl cyclase assay. Thus, 8 is able to bind to and stimulate 5-HT 1A -receptors. The results are discussed in relation to a previously described 3-D model for 5-HT 1A -receptor agonists.

Stereoselectivity of Drug Receptor Interactions

Recent results in studies of interactions between dopamine receptors and stereoselective agonists and antagonists are reviewed. Also discussed are the stereoselectivity of seotonergic 5-HT1A-receptor agonists and some of the difficulties associated with modeling the interaction between ligands and receptors on a molecular level