Rainer Dorow

Dual action on central dopamine function of transdihydrolisuride, a 9, 10-dihydrogenated analogue of the ergot dopamine agonist lisuride

Abstract Transdihydrolisuride (TDHL), a 9, 10-dihydrogenated analogue of the ergot dopamine (DA) agonist lisuride (LIS), was investigated for its influence on central dopaminergic functions in rats and mice after single i.p. administration. TDHL (0.39–25 mg/kg) unexpectedly induced catalepsy and antagonized apomorphine-induced stereotypes in rats; it was approx. 3–5 times less potent than the DA antagonist haloperidol. TDHL (0.025–6.25 mg/kg) caused hypokinesia and antagonized the apomorphine-induced hyperactivity in rats. Pre-treatment with TDHL (0.78–12.5 mg/kg) which per se did not alter thermoregulation at room temperature, antagonized the hypothermia induced by the DA agonist apomorphine (5 mg/kg i.p.) in mice. These DA antagonistic properties contrasted with the prolactin (PRL) lowering effect of TDHL (0.01–10 mg/kg p.o.) in reserpinized female rats thus indicating DA agonist function. PRL inhibition tended to be longer lasting (>8h) than after LIS (0.01–1 mg/kg p.o.) with comparable potency. In healthy volunteers TDHL (0.2–1 mg p.o.) effectively lowered PRL levels with similar potency but with a markedly longer duration of action than LIS (>24h after 0.5 mg TDHL). In contrast to the side effects after acute LIS treatment, no comparable adverse reactions such as nausea, emesis or postural hypotension typical for DA agonists could be observed with effective PRL lowering doses of TDHL. The unique profile of TDHL on DA functions suggests its usefulness as a potent, longlasting PRL inhibitor with less unwanted effects. The behavioural findings indicate the potential usefulness of TDHL as a neuroleptic, which due to its partial DA agonistic action, should lack typical extrapyramidal or neuroendocrine side effects of classic DA receptor blocking agents. Possible implications of the dual function of TDHL upon central DA receptors are discussed with regard to the incidence of side effects or selectivity of action for other conceivable therapeutic indications.

Human studies on the benzodiazepine receptor antagonist β-carboline ZK 93 426: antagonism of lormetazepam's psychotropic effects

The effects of lormetazepam (0.03 mg/kg IV) a benzodiazepine (BZ) derivative in combination with ZK 93 426 (0.04 mg/kg IV) a β-carboline, benzodiazepine receptor antagonist were evaluated in humans. Independently, the effects of ZK 93 426 on its own were investigated. A psychometric test battery to evaluate sedation (visual analog scales (VAS), anxiolysis (state-trait-anxiety inventory scale (STAIG X1) and cognitive functions [logical reasoning test (LR), letter detection test (LD)] was applied before and several hours after initiation of treatment. Multiple sleep latency test (MSLT), which measures day time sleepiness, was also applied. Vigilosomnograms analysed from standard EEG recordings were evaluated shortly before and for 1 h after treatment. Treatment started with an intravenous injection of either lormetazepam (LMZ) or placebo (PLA), which was followed 30 min later by administration of either ZK 93 426 or placebo; thus four treatment groups were created (PLA + PLA, LMZ + PLA, LMZ + ZK 93 426 and PLA + ZK 93 426). ZK 93 426 antagonized the sedative and hypnotic effect of LMZ as estimated by MSLT and vigilosomnograms, respectively. Impairment of cognitive functions (LR and LD) induced by LMZ was also antagonized by ZK 93 426. ZK 93 426 had no effect on the changes in the time estimation seen in the LMZ group. Furthermore, ZK 93 426 on its own increased vigilance (alertness) as measured by the vigilosomnogram. A competitive antagonism at the benzodiazepine binding site between ZK 93 426 and LMZ is suggested by their combination effects; the intrinsic activity of ZK 93 426 seems to be due to its weak partial inverse agonist component.

Novel 8 α-ergolines with inhibitory and stimulatory effects on prolactin secretion in rats

Abstract Four derivatives of the ergot dopamine (DA) agonist lisuride (LIS), namely 6-n-propyl-lisuride (6-n-propyl-LIS), transdihydrolisuride (TDHL), 6-n-propyl-transdihydrolisuride (6-n-propyl-TDHL) and 2-bromolisuride (2-Br-LIS) were investigated in female rats with regard to their influence on hyperprolactinaemia induced by pretreatment with reserpine (2 mg/kg i.p., 24 h) at various intervals following their subcutaneous or oral administration (0.05 mg/kg). Two hours after administration, LIS, 6-n-propyl-LIS, and 6-n-propyl-TDHL caused a statistically significant inhibition of reserpine-induced hyperprolactinaemia of about the same extent. Eight hours after administration 6-n-propyl-LIS and 6-n-propyl-TDHL were as active as after 2 h in inhibiting prolactin (PRL) secretion whereas LIS was almost ineffective in this respect. TDHL caused a statistically significant inhibition of PRL secretion at 2 and 8 h after oral administration; this effect was less pronounced after s.c. administration. In contrast to the aforementioned derivatives 2-Br-LIS further increased the reserpine-induced hyperprolactinaemia. In normal male rats pretreatment with 2-Br-LIS (0.025–6.25 mg/kg s.c., 2 h) dose-dependently stimulated PRL secretion. The present data support the assumption of the longlasting DA agonistic action of 6-n-propyl-LIS and 6-n-propyl-TDHL and of the antidopaminergic properties of 2-Br-LIS recently derived from behavioural studies.

Scopolamine-induced amnesia in humans: lack of effects of the benzodiazepine receptor antagonist β-carboline ZK 93426.

It has been suggested from pharmacological studies in animals that ZK 93426 may improve memory and other cognitive processes in humans. Scopolamine has been used to model aspects of memory impairment. To test the effects of ZK 93426 alone and in combination with scopolamine, ZK 93426 (0.04 mg/kg) or vehicle (Intralipid R) was administered intravenously (i.v.) to normal controls, pre-treated with either scopolamine 0.5 mg administered subcutaneously (s.c.) or the same volume of saline. A visual (presentation of pictures) and a verbal (words list) memory test were applied. Both drugs on their own and in combination were found to be safe and well tolerated. ZK 93426 did not antagonize the scopolamine-induced impairment of acquisition of the words list. Scopolamine did not impair delayed recall of visual or verbal material. ZK 93426 alone improved performance in delayed recall of visual material presented after drug application, whereas it impaired performance in delayed recall of visual material presented before drug administration.

Effect of the new ergot derivative terguride on plasma PRL and GH levels in patients with pathological hyperprolactinemia or acromegaly.

Terguride, a derivative of lisuride, has been shown to possess a mixed dopaminergic-antidopaminergic activity in experimental models. We have studied the effects on PRL and GH levels of 0.2 mg po of terguride in 8 normal subjects, in 15 patients with pathological hyperprolactinemia (PHP) and in 17 patients with active acromegaly. In PHP, PRL levels were significantly reduced up to 300 min after terguride with a nadir (45 ± 4.0 % SE) significantly lower (p< 0.05) than the one observed in the 8 normal subjects (72 ± 3.5%). There was no significant difference in plasma PRL levels after 0.2 mg terguride or lisuride in 7 out of 15 patients tested with both drugs. Terguride did not significantly modify GH levels in PHP and in normals but when considering basal and peak (occurring between 60 and 150 min) GH values, a significant difference was found (p< 0.01 ). Mean peak of GH did not differ significantly between PHP (5.0 ± 1.1 ng/ml) and normals (6.8 ± 1.7 ng/ml). Plasma GH levels of 17 acromegalics were not modified by 0.2 mg of terguride but were significantly reduced by 2.5 mg of bromocriptine. Terguride and bromocriptine reduced PRL levels in acromegalics (p< 0.01 ) without any significant difference between the two drug. 0.2 mg terguride b i d given for 15 days to 7 healthy volunteers significantly reduced both basal and sulpiride (25 mg im) — stimulated PRL levels. Side effects were observed only in 4 out of 47 subjects tested with terguride and in 8 out of 34 tested with bromocriptine.