Uli Hacksell

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.

3-PPP, a new centrally acting DA-receptor agonist with selectivity for autoreceptors

Abstract The new dopamine (DA) analogue 3-(3-hydroxyphenyl)-N-n-propyl-piperidine, 3-PPP, synthesized in our laboratories, is a central DA-receptor agonist with a pharmacological profile indicative of preferential DA-autoreceptor interactions. This is suggested by the following experimental evidence: 1. a) 3-PPP causes a selective, dose-dependent decrease in rat brain DA-synthesis rate which can be blocked by haloperidol, 2. b) 3-PPP retards brain DA utilization (blocked by haloperidol), 3. c) 3-PPP dose-dependently suppresses spontaneous locomotor activity; the suppression is accompanied by reduced brain DOPAC levels and can be counteracted by an “autoreceptor” dose of haloperidol, 4. d) 3-PPP consistently fails to produce any signs of postsynaptic DA-receptor activation, as indicated by the absence of hypermotility and stereotypies, failure to antagonize the reserpine syndrome and failure to induce ipsilateral turning in unilaterally striatum-lesioned rats. In addition, 3-PPP does not affect the behavioural effects resulting from postsynaptic DA-receptor activation by apomorphine. In conclusion, 3-PPP appears to be a centrally acting, selective DA-autoreceptor agonist. It may prove useful as a tool for elucidating dopaminergic functions and in the treatment of psychotic disorders and other diseases states possibly associated with disturbances in central DA transmission.

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.

The chemistry and biochemistry of C-nucleosides and C-arylglycosides

Publisher Summary This chapter reviews recent advances in the chemistry and biochemistry of C-nucleosides, the literature concerning C-arylglycoside (i.e., nonnitrogen heterocyclic C-nucleoside) antibiotics, and recent significant advances in the synthesis of C-nucleosides and C-glycosides. It also discusses biological test data and data that are relevant to structure–activity relationships. Modification of readily available natural C-nucleosides is an attractive route to new C-nucleoside analogs and derivatives, because one starting material often possesses much of the desired functionality and chiral properties. The chapter illustrates this approach with examples. The most frequently used strategy for C-nucleoside synthesis involves the construction of a heterocyclic aglycone from the C-1 substituent of a functionalized sugar intermediate.

The 5-HT1A receptor selective ligands, (R)-8-OH-DPAT and (S)-UH-301, differentially affect the activity of midbrain dopamine neurons

SummaryThe effects of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2(di-n-propylamino)tetralin [(R)-8-OH-DPAT] and the novel 5-HT1A antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] were studied with regard to the firing pattern of single mesencephalic dopamine (DA) neurons with extracellular recording techniques in chloral hydrate anesthetized male rats. Neuronal activity was studied with respect to firing rate, burst firing and regularity of firing. In the ventral tegmental area (VTA) low doses of (R)-8-OH-DPAT (2–32 μg/kg i.v.) caused an increase in all three parameters. The effect on firing rate of DA neurons was more pronounced in the parabrachial pigmentosus nucleus than in the paranigral nucleus, the two major subdivisions of VTA. In the substantia nigra zona compacta (SN-ZC), (R)-8-OH-DPAT (2–256 μg/kg i.v.) had no effect on firing rate and regularity of firing and only slightly increased burst firing. High doses of (R)-8-OH-DPAT (512–1024 μg/kg i.v.) decreased the activity of DA cells in both areas, an effect that was prevented by pretreatment with the selective DA D2 receptor antagonist raclopride. (S)-UH-301 (100–800 μg/kg i.v.) decreased both firing rate and burst firing without affecting regularity of DA neurons in the VTA. In the SN-ZC, (S)-UH-301 decreased the firing rate but failed to affect burst firing and regularity of firing. These effects of (S)-UH-301 were blocked by raclopride pretreatment. Local application by pneumatic ejection of 8-OH-DPAT excited the DA cells in both the VTA and the SN-ZC, whereas (S)-UH-301 inhibited these cells when given locally. These results show that 5-HT1A receptor related compounds differentially affect the electrophysiological activity of central DA neurons. The DA receptor agonistic properties of these compound appear to contribute to the inhibitory effects of high doses of (R)-8-OH-DPAT and (S)-UH-301 on DA neuronal activity. Given the potential use of 5-HT1A receptor selective compounds in the treatment of anxiety and depression their effects on central DA systems involved in mood regulation and reward related processes are of considerable importance.

Identification of 15-Hydroperoxyabietic Acid as a Contact Allergen in Portuguese Colophony

Abstract— 15‐Hydroperoxyabietic acid (15‐HPA) has been isolated from Portuguese colophony of the gum rosin type and identified as its methyl ester. The structure of the compound was elucidated using UV, IR, NMR and mass spectrometry. 15‐HPA methyl ester was found to be an elicitor when tested in colophony‐sensitized guinea‐pigs. The sensitizing capacity was verified in the same species and 15‐HPA methyl ester was considered to be a strong allergen. The eliciting potential was also verified in patients with known allergy to colophony. The Portuguese gum rosin investigated contained approximately 1% of 15‐HPA. Based on its allergenicity and the amounts isolated, we conclude that 15‐HPA is a main contact allergen in Portuguese gum rosin.

The 5-HT1A receptor antagonist (S)-UH-301 augments the increase in extracellular concentrations of 5-HT in the frontal cortex produced by both acute and chronic treatment with citalopram.

In a recent study, utilizing single cell recording techniques, we have shown that administration of 5-HT1A receptor antagonists, e.g. (S)-UH-301, to rats concomitantly treated, acute or chronically, with the selective serotonin reuptake inhibitor (SSRI) citalopram significantly increases the activity of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN). Here we report correlative experiments using microdialysis in freely moving animals to measure extracellular levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex, a major projection area for DRN-5-HT neurons. Acute administration of (S)-UH-301 (2.5 mg/kg s.c.) or citalopram (2.0 mg/kg s.c.) increased 5-HT concentrations with a maximum of about 70% and 185%, respectively, above baseline. However, when (S)UH-301 was administered 30 min before citalopram the maximal increase in 5-HT levels was approximately 400%. In rats chronically treated with citalopram (20 mg/kg/day i.p. for 14 days) basal 5-HT concentrations in the frontal cortex were significantly increased and 5-HIAA concentrations were decreased when measured 10–12 h, but not 18–20 h, after the last injection of citalopram, as compared to basal 5-HT and 5-HIAA concentrations in chronic saline-treated rats. When (S)-UH-301 (2.5 mg/kg s.c.) was administered 12 h, but not 20 h, after the last dose of citalopram it produced a significantly larger increase in extracellular concentrations of 5-HT than in control rats. However, in rats pretreated with a single, very high dose of citalopram, 20 mg/kg i.p., administration of (S)-UH-301 at 12 h after citalopram did not increase 5-HT levels.The augmentation by (S)-UH-301 of the increase in brain 5-HT output produced by acute administration of citalopram is probably due to antagonism of the citalopram induced feedback inhibition of 5-HT cells in the DRN, as previously suggested. However, the capacity of (S)-UH-301 to further increase the already elevated extracellular concentrations of 5-HT in brain in animals maintained on a chronic citalopram regimen, in which significant tolerance to the initial feedback inhibition of DRN-5-HT cells had developed, represents a novel finding. Generally, the reduced feedback inhibition of 5-HT neurons obtained with chronic citalopram treatment, and the associated elevation of brain 5-HT concentrations, may be related to functional desensitization of somatodendritic 5-HT1A autoreceptors in the DRN. This phenomenon may also largely explain the larger increase in 5-HT output produced by (S)-UH-301 in chronic citalopram treated animals as compared to its effect in control animals. Yet, a contributory factor may be a slight, remaining feedback inhibition of the 5-HT cells caused by residual citalopram at 12, but not 20 h after its last administration.Previous clinical studies suggest that addition of a 5-HT1A receptor antagonist to an SSRI in the treatment of depression may accelerate the onset of clinical effects. Moreover, in therapy-resistant cases maintained on SSRI treatment, addition of a 5-HT1A receptor antagonist may improve clinical efficacy. Since the therapeutic effect of SSRIs in depression has been found to be critically linked to the availability of 5-HT in brain, our experimental results support, in principle, both of the above clinically based notions.

5-HT1A receptor antagonists increase the activity of serotonergic cells in the dorsal raphe nucleus in rats treated acutely or chronically with citalopram

In this study we have examined the acute effects of systemic administration of the selective serotonin reuptake inhibitor (SSRI), citalopram, in combination with either of the two selective 5-HT1A receptor antagonists, (S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin [(S)-UH-301] or (+)-N-tertbutyl 3-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylpropionamide dihydrochloride [(+)-WAY100135], on the activity of single 5-HT neurons in the dorsal raphe nucleus (DRN) of anesthetized rats using extracellular recording techniques. Acute administration of citalopram (0.3 mg/kg i.v.) significantly decreased the firing rate of DRN-5-HT cells most likely as a result of indirect stimulation of inhibitory somatodendritic 5-HT1A autoreceptors located on 5-HT cells in the DRN. This effect of citalopram was completely reversed by (S)-UH-301 (0.5 mg/kg i.v.) and partly by (+)WAY100135 (0.5 mg/kg i.v.). Furthermore, the inhibitory effect of citalopram on the activity of 5-HT neurons was significantly attenuated by pretreatment with (S)-UH-301 (0.25 mg/kg i.v.) or (+)-WAY100135 (0.25 mg/kg i.v.).We have also studied the effects of (S)-UH-301 (0.03–0.50 mg/kg i.v.) on the firing rate of single DRN5-HT cells in rats chronically treated with citalopram (20 mg/kg/day i.p. × 14 days). Administration of (S)UH-301 significantly and dose-dependently increased the activity of 5-HT cells in citalopram-treated rats, but did not affect these neurons in saline-treated (1 m1/kg/day i.p. × 14 days), control rats. Our results thus suggest that 5-HT1A receptor antagonists can augment both the acute and chronic effects of citalopram on central serotonergic neurotransmission. Since the antidepressant effect of SSRIs is critically linked to the availability of 5-HT, these findings support the notion that 5-HT1A receptor antagonists may not only shorten the latency of onset of SSRIs in the treatment of depression, but also increase their efficacy.

Contact allergy to dehydroabietic acid derivatives isolated from Portuguese colophony

7‐oxodehydroabietic acid and 15‐hydroxydehydroabietic acid were isolated as their methyl esters from Portuguese colophony of the gum rosin type and identified as contact allergen. Another oxidation product of dehydroabietic acid, 15‐hydroxy‐7‐oxodehydroabietic acid, was synthesized and identified as a component of Portuguese gum rosin. 7‐oxodehydroabietic acid was found to a be a grade III allergen according to the GPMT method. Guinea pigs induced with gum rosin showed only a low response to the isolated compounds, while patients with a known allergy to gum rosin reacted to a greater extent. The result imply that the content of oxidized dehydroabietic acids in gum rosin is too low to give a marked sensitization in the animals. However, the patients might have come in contact with the allergens in technically modified rosins. The compounds showed a pattern of cross‐reactivity in the animal experiments as well as among the patch tested patients.