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Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D1 receptor agonists or selective dopamine D2 receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D1 agonistic and D2 antagonistic effects, 9,10-didehydro- N-methyl- N-(2-propynyl)-6-methyl-8beta-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats. Pretreatment with systemic injections of LEK-8829 attenuated reinstatement of cocaine-seeking induced by cocaine priming injections and diminished cocaine intake in cocaine self-administration sessions. LEK-8829 itself did not induce reinstatement of cocaine-seeking and did not maintain intravenous self-administration. The results of our study indicate that LEK-8829 is a candidate medication for the treatment of cocaine craving in cocaine addiction.

The contraction/relaxation responses of thoracic aortal rings clamped with two clamping pressures to potassium chloride (KC1), noradrenaline and carbachol were studied using a scanning electron microscope (SEM) to ascertain endothelial lacerations. Clamp A had the tip pressure PA = 0.60 N/mm2 and clamp B PB = 5.16 N/mm2. In 15 Wistar albino rats, weighing 328 +/- 19 g (mean +/- SD), the thoracic aorta was occluded for 15 min and then three vascular rings (2 mm wide) were excised. The proximal unclamped ring served as a control. The aorta diameter was calculated from the circumference of distal rings 1.61 +/- 0.01 mm (n = 15, dmin = 1.51 mm, dmax = 1.70 mm). The rings were challenged with cumulative additions of KC1 (10-80 mmol/l) to measure the contraction. Then cumulative relaxation on the administration of carbachol (0.01-100 mumol/l) as a response to noradrenaline precontraction (0.1 mumol/l) was determined. A significant loss (P < 0.05) of vascular relaxation in all clamped rings (clamped with PA and PB clamping pressures) was seen. No significant differences (P > 0.05) were observed for contraction between clamped and control rings clamped with clamp A, however the rings clamped with clamp B showed significantly reduction of contraction (P < 0.05). No significant differences were seen from control rings between groups A and B (P > 0.05), as well as from clamped rings between groups A and B (P > 0.05) for both the contraction and relaxation parts of the experiments. With SEM, great endothelial lacerations with complete disruption of the endothelial layer in the rings clamped with the clamp B were seen, but no disruption in rings clamped with clamp A. Therefore endothelial vascular layers are much more susceptible to pressure injuries than was previously believed. The clamped vessel wall injuries, particularly in endothelial layers, depend on the momentary peak clamping pressure (MPCP) as well as on the lower stationary clamping pressure (SCP).

In a structure-activity study, carried out in rabbit isolated aorta, the effect of different structural modifications in the ergoline nucleus upon the activity at 5-HT₂ receptors and α-adrenoceptors was determined. 9,10-didehydro – N- methyl – N- (2-propynyl) – 6 – methylergoline – 8 β-carboxamide (LEK 8842) was chosen as the basic backbone of this study. The parent compound LEK 8842 showed strong α-adrenoceptor agonistic activity and partial 5-HT₂ receptor agonistic activity, and its potency (pD₂ = 6.41) was comparable with that of 5-hydroxytryptamine (5-HT, pD₂ = 6.84) and noradrenaline (pD₂ = 6.82). Hydrogenation of the double bond in the position 9,10 (LEK 8822) attenuated the potency (pD₂ = 5.35) as well as the intrinsic activity on α-adrenoceptors and eliminated 5-HT₂ receptor agonistic activity. LEK 8822 acted on the α-adrenoceptors not only as a partial agonist but also as a competitive antagonist of responses elicited by noradrenaline. When tested against 5-HT, LEK 8822 acted as an antagonist. Bromination in position 2 yielded the derivative LEK 8841 with no agonistic activity at concentrations up to 3 μmol/l, yet the affinity for 5-HT₂ receptors and α-adrenoceptors was preserved. LEK 8841 was the only one that acted as pure simple competitive antagonist of responses elicited by 5-HT (pA₂ = 7.93) and noradrenaline (pA₂ = 6.45). Its activity was qualitatively similar to that observed with the 5-HT₂/α-adrenoceptor antagonist ketanserin which was tested for comparison. Concerning selectivity for 5-HT₂ receptors versus α-adrenoceptors, LEK 8841 proved to be more selective for 5-HT₂ receptors than ketanserin. pA₂ values for ketanserin antagonistic activity to 5-HT and to noradrenaline were 8.22 and 7.48, respectively. Finally, quaternization in the N(6) position (LEK 8827) almost completely eliminated affinity for 5-HT₂ receptors and for α-adrenoceptors. This study has shown that relatively small modifications in the structure of the ergoline system led to pronounced changes in the affinity as well as intrinsic activity at both receptors studied.

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