Posted by CrAzYmEd on May 23, 2010, at 7:18:25 [reposted on May 24, 2010, at 22:41:53 | original URL]
Allright guys, i posted this on several message boards because i beleive that lisuride has incredible potential for anhodonia, social anxiety, depression etc.
Lets take a look at its pharmacological profile:
[QUOTE]Mode of actionLisuride is a dopamine and serotonin receptor partial agonist. It has a high affinity for the dopamine D2, D3 and D4 receptors, as well as serotonin 5-HT1A[1] and 5-HT2A/C receptors.[2] While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoloid N,N-diethyl-lysergamide (LSD), it lacks the psychedelic effects of its sister compound.[3][/QUOTE]
While its only a partional agonist, this looks pretty interesting to me, does anyone have the percentage of intrinsic activity?[QUOTE][Anxiolytic effects of lisuride and its agonistic action to central 5-HT1A receptors]
[Article in Japanese]Akai T, Takahashi M, Nakada Y, Ohnishi R, Ikoma Y, Yamaguchi M.
Research Department, Nihon Schering K.K., Osaka, Japan.
Abstract
Effects of lisuride, a derivative of ergot alkaloid, on central 5-HT1A receptors were investigated biochemically, behaviorally and electroencephalographically (EEG) in rats and rabbits. Effects of lisuride in water-lick conflict tests were also investigated in rats. Lisuride was found to strongly inhibit the bindings of [3H]8-OH-DPAT to 5-HT1A receptors in the raphe nucleus, hippocampus, cortex, amygdala and hypothalamus of rat brain. Inhibitory effects of lisuride on bindings of [3H]8-OH-DPAT in the hippocampus was almost the same as that of 5-HT (Ki = 0.5 nM) and stronger than those of the 5-HT agonist 5-MeO-DMT (Ki = 2.1 nM) or other ergot derivatives (bromocriptine and pergolide, Ki = 3.0 nM). Lisuride (0.1-0.5 mg/kg, i.p.), like 8-OH-DPAT, dose-dependently induced a 5-HT behavioral syndrome in rats. Lisuride affected locomotor activity in rats, whereas 8-OH-DPAT did not. In hippocampal EEG of rabbits, lisuride (0.01-0.03 mg/kg, i.v.), like 8-OH-DPAT and diazepam, dose-dependently inhibited rhythmical slow activity (RSA) induced by acoustical stimulation (3100 Hz) and also inhibited the RSA increased by administration of anxiogenic FG7142. In water-lick conflict tests, lisuride (0.05-0.1 mg/kg, i.p.), like diazepam, increased the number of shocks. These findings indicated that lisuride acts as a strong agonist on central 5-HT1A receptors and suggested that lisuride might be a potential anxiolytic.[/QUOTE][quote][Therapeutic effect of lisuride maleate on post-stroke depression]
[Article in Japanese]Hougaku H, Matsumoto M, Hata R, Handa N, Imaizumi M, Sugitani Y, Yoneda S, Etani H, Sueyoshi K, Kusunoki M, et al.
First Department of Medicine, Osaka University Medical School.
Abstract
Twenty post-stroke depressive patients who obtained more than 11 points on Self-Rating Questionnaire for Depression, were treated with 0.075 mg/day lisuride maleate for 12 weeks. The drug effect on depression was evaluated quantitatively by the Hamilton Rating Scale for Depression. The relationships between brain CT or MRI and SRQ-D score were investigated in 24 subjects. More than 80% of post-stroke depressive patients improved after lisuride maleate treatment for 8 or 12 weeks. In particular, depressed mood, hypobulia, sleep disturbance, anxiety, etc. were significantly improved compared to the baseline condition. As for the relationships with CT and/or MRI findings, the group with moderate to severe brain atrophy had a significantly higher grade of depressive state than those without.[/quote]
80% of the patients recovered, wich is quite remarkable.It makes sense tough since its pharmacological profile is nearly perfect when it comes to depression, combined 5HT2A, 5HT1A, 5HT2C (strangely agonism of this receptor is antidepressive) D2, D3, D4 agonism.
[QUOTE] Indeed, 8-OH-DPAT induced spontaneous 'tail-flicks' in the absence of external stimulation. This property was shared by lisuride and LSD, which also have high intrinsic activity at 5-HT1A sites. [/QUOTE]
[url]http://www.ncbi.nlm.nih.gov/pubmed/2533334[/url]High intrinsic activity sounds good.
[QUOTE]Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine1A receptor-mediated behavioral effects overlap its other properties in rats
(1) Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907, USA,
Received: 11 February 2002 Accepted: 29 April 2002Abstract
Rationale. There is substantial evidence that lisuride can produce effects linked to 5-HT1A receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT2A/2C receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT1A receptors has been demonstrated in several different laboratories and that activation of 5-HT1A and 5-HT1B receptors can modulate dopaminergically mediated responses.
Objective. The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature.
Results. In drug discrimination studies, lisuride fully mimicked the 5-HT1A agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for ( )-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT1A receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT1A antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT1A agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.
Conclusion. We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT1A receptors.[/QUOTE][quote]lisuride: 4.00 5ht1a, 3.88 Alpha2C, 3.78 Alpha2B, 3.22 Alpha2A, 3.01 5ht2b, 2.99 5ht5a, 2.90 D4, 2.74 5ht2a, 2.65 D2, 2.64 5ht7, 2.61 5ht6, 2.56 Beta1, 2.27 5ht1b, 2.09 Alpha1A, 1.93 Beta2, 1.83 5ht1e, 1.59 D5, 1.42 H2, 1.34 D3, 1.08 Alpha1B; 0.00: 5ht1d, 5ht2c, D1, DAT, NET, Imidazoline1, M1, SERT, CB2, KOR, MOR, M3, M2, M5, M4, CB1, Ca Channel; ND: Sigma1, H1, Sigma2, DOR, NMDA[/quote]
[url="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009019"]http://www.plosone.org/article/info:doi/10...al.pone.0009019[/url]I dont know how to read those affinities tough.
They dont clarify wheter its a agonist or antagonist, just the affinities.
While it seems to bind with the 5HT2B receptors, it acts as antagonist on them.
[quote]Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis.
Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B.Global Medical Safety, Schering AG, Berlin, Germany. [email]christoph.hofmann@schering.de[/email]
Abstract
OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.[/quote]Also the findings that it interacts with several adrenergic receptors and 5HT6 and 5HT7 is interesting.
EDIT:
[quote]It is also useful to present the npKi data of Fig. S2 in numerical format. In the listing below, the npKi values for each drug are arranged in decreasing order. A value of 0.00 means that the Ki value was measured as >10,000 nm. ND indicates that the data is not available. The 5-HT2A and 5-HT2C receptors are also highlighted in bold font for easier location. [b]npKi values below about 2.0 should be imperceptible, while values above about 2.0 should be perceptible, and the higher the npKi value, the more perceptible a receptor should be.[/b][/quote]
So basicly, this is what counts:
lisuride: 4.00 5ht1a, 3.88 Alpha2C, 3.78 Alpha2B, 3.22 Alpha2A, 3.01 5ht2b, 2.99 5ht5a, 2.90 D4, 2.74 5ht2a, 2.65 D2, 2.64 5ht7, 2.61 5ht6, 2.56 Beta1, 2.27 5ht1b, 2.09 Alpha1A,So, what i gathered
Lisuride is a:
5HT1A agonist
5HT1B agonist
5HT2A agonist
5HT2C agonist
5HT6 agonist
5HT7 antagonist
5HT5A didnt find yet
D2 agonist
D4 agonistAccording to the journal not significant:
5ht1e
D5
H2
D3Other adronergic receptors not sure yet.
[QUOTE][Effects in animal models of depression of lisuride alone and upon coadministration with antidepressants]
[Article in Japanese]Nakamura K, Ikoma Y, Kimura K, Nakada Y, Kobayashi S, Yamaguchi M, Nakagawa H.
Research Department, Nihon Schering K.K., Osaka, Japan.
Abstract
Effects of lisuride, a central dopamine and serotonin agonist of the ergot type, in animal models of depression were investigated in comparison with those of desipramine, mianserin and rolipram. Lisuride, like desipramine and mianserin, inhibited reserpine-induced hypothermia in mice (0.5-5.0 mg/kg, i.p.) and suppressed muricide in olfactory bulbectomized rats (ED50 = 0.16 mg/kg, i.p.) in a dose-dependent manner. The anti-muricidal effect was slightly enhanced by the repeated administration of 0.25 mg/kg lisuride. Lisuride (0.05-0.25 mg/kg, i.p.), like desipramine, dose-dependently reduced the duration of immobility in rats forced to swim, and this effect was antagonized by haloperidol. The reduction of immobility time was enhanced by the repeated administration of lisuride; at the same time, the ambulation in rats increased. Furthermore, the immobility-reducing effects of desipramine and rolipram were markedly enhanced by the co-administration of a low dose of lisuride (0.025 mg/kg, i.p.), which by itself had no effect on the immobility time. These results indicate that lisuride may be useful for the treatment of depression and indicate that a low dose of lisuride may enhance the clinical effectiveness of antidepressants such as desipramine.[/QUOTE]
poster:CrAzYmEd
thread:948688
URL: http://www.dr-bob.org/babble/neuro/20100223/msgs/948688.html