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Objectives: To enumerate peri-implant bone strain pattern under quantified occlusal load and verify the bone response through comparison with the critical strain thresholds defined by Frost's bone mechanostat theory., Material and Methods: Mandibular unilateral recipient sites in two greyhound dogs were established with posterior teeth extractions. After 6 weeks, four titanium implants were placed in each dog mandible. Following 12 weeks of healing, successfully osseointegrated implants were placed in supra-occlusal contact via screw-retained non-splinted metal crowns. Plaque control and a dental health enhancing diet were prescribed. A bite force detection device was used to quantify in vivo occlusal load as the dogs functioned with supra-occlusal contact. After 8 weeks, the dogs were sacrificed. In vitro peri-implant bone strain under quantified occlusal load was measured using bonded stacked rosette strain gauges., Results: The average and peak in vivo occlusal load measured were 434 and 795 newton (N). When individually and simultaneously loaded in vitro (≤476 N), absolute bone strains up to 1133 and 753 microstrains (με) were measured at implant apices, respectively. Bone strain reaching 229 με was recorded at distant sites. For bone strain to reach the pathological overload threshold defined by Frost's bone mechanostat theory (3000 με), an occlusal load of 1344 N (greater than peak measured in vivo) is required based on the simple linear regression model., Conclusion: Under the in vivo and in vitro conditions investigated in this study, peri-implant bone was not found to be under pathological overload following supra-occlusal contact function. Strain dissipation to distant sites appeared to be an effective mechanism by which implant overload was avoided., (© 2012 John Wiley & Sons A/S.) more...

Different putative toxic amyloid beta (A beta) peptides, beta (1-42), beta (1-40) and beta (25-35), were infused (0.75, 1.5 or 3 nmol) in the rat medial septum. Memory deficits were then investigated using the social recognition test. A significant amnesia was observed 4, 7 and 14 days after intraseptal injection of 3 nmol of beta (1-42), beta-(1-40)- and beta (25-35). Lower amounts of beta (1-42) were inactive except 1.5 nmol that disrupted memory 7 days post-treatment. Used as control, the inverted peptide beta (40-1) and the scrambled beta (25-35) were inactive. Using the prolongation procedure, rats infused with 3 nmol of beta (1-40) were still able to recognize the same juvenile. Finally, a daily treatment with the non-peptide neurotrophic compound SR 57746A (10 mg/kg p.o.) over 21 days, prevented the deficits in short-term memory induced by the intraseptal infusion of 3 nmol of either beta (1-40) or beta (25-35). These findings suggest that A beta fragments could impair short-term memory when infused in the rat medial septum, an effect that is prevented by SR 57746A. more...

The cholinergic activities of SR 46559A, 3-[N-(2 diethyl-amino-2-methylpropyl)-6-phenyl-5-propyl] pyridazinamine sesquifumarate, have been investigated in vitro and in vivo, in rodents. Using rat brain cortical membranes, SR 46559A was a competitive ligand (Ki = 112 nM) at muscarinic M1 receptors, its affinity for muscarinic M2 (cardiac) and M3 (glandular) receptors being 6-7 times lower. SR 46559A did not interact with brain nicotinic receptors and high affinity choline uptake sites nor did it inhibit brain acetylcholinesterase activity. In contrast to reference muscarinic agonists, SR 46559A (1 mM) did not inhibit the forskolin-induced activation of cAMP synthesis nor did it stimulate phosphoinositides breakdown in various brain preparations. However, this compound enhanced (+67% at 1 mM) diacylglycerol formation in rat striatal miniprisms, an effect fully reversed by atropine. As shown with reference agonists, SR 46559A inhibited (IC50 = 10 microM) the K(+)-evoked release of [3H]GABA from rat striatal slices and reduced at 0.5 and 1 microM, the population spike amplitude of the CA1 pyramidal cells induced by stimulation of the Schaffer's collateral commissural pathway in rat hippocampal slices. In mice, SR 46559A at a near lethal dose (200 mg/kg PO) did not induce the typical cholinergic syndrome nor did it modify at 30 mg/kg PO the oxotremorine-induced hypothermia. Like muscarinic agonists, SR 46559A (1 mg/kg PO) potentiated haloperidol-induced catalepsy in rats and inhibited (ED50 = 0.12 mg/kg PO) rotations induced in mice by intrastriatal injection of pirenzepine.(ABSTRACT TRUNCATED AT 250 WORDS) more...

The effects of a chronic treatment (21 days) with the acetylcholinesterase (AChE) inhibitor tetrahydroaminoacridine (THA) on muscarinic receptors subtypes were investigated at various times after the last administration of the drug, in various brain areas including cortex, striatum, hippocampus and cerebellum. Forty eight hours after the end of chronic THA treatment, the number of muscarinic receptors, labelled with [(3)H]NMS, was significantly lowered in the cortex and the striatum but not in the hippocampus or cerebellum. High affinity pirenzepine binding sites (M(1) receptors), directly assayed using [(3)H]pirenzepine saturation assays or estimated by pirenzepine [(3)H]NMS competition, were lowered only in the cortex and in the striatum of THA-treated rats. In contrast, the number of low affinity pirenzepine sites (M(2) receptors), was not significantly modified. At shorter wash-out period (18 h), the density of M(1) receptors decreased by 26, 46 and 52% in the hippocampus, cerebral cortex and striatum, respectively. In all cases, K(d) values remained unchanged suggesting that the loss of M(1) sites was not due to a modification of radioligand affinity for the receptors. Although THA displayed a micromolar affinity for M(1) and M(2) receptors in vitro, this AChE inhibitor did not interfere with the receptor assays since no trace of residual free THA was detected in rat brain at 48 h post-treatment. These results suggest that chronic treatment with THA produced a selective down-regulation of M(1) receptors; they also indicate that these receptors may be regulated differently in cortical, striatal, hippocampal or cerebellar regions. more...

In rodents, SR 95191 [3-(2-morpholinoethylamino)-4-cyano-6-phenylpyridazine] has been shown to be active in animal models of depression. The profile of activity of SR 95191 suggests that the compound is a selective and short-acting type A monoamine oxidase (MAO) inhibitor (MAOI) in vivo. In the present study, the interaction of SR 95191 with MAO-A and MAO-B activity was further examined in vivo and in vitro. In brain, liver, and duodenum of pretreated rats, SR 95191 selectively inhibited MAO-A (ED50 = 3-5 mg/kg, p.o.), whereas MAO-B was only weakly inhibited for doses as high as 300 mg/kg, p.o. In vivo, SR 95191 (1-100 mg/kg, p.o.) antagonized, in a dose-dependent fashion, the irreversible inhibition of brain and liver MAO-A induced by phenelzine. Finally, dopamine and 5-hydroxytryptamine depleted from their striatal stores by tetrabenazine were able to displace SR 95191 from the active site of MAO-A. However, ex vivo, kinetic studies showed that the inhibitory effect of SR 95191 (1-10 mg/kg) towards MAO-A was noncompetitive and was unchanged after dilution or dialysis. In vitro, the inhibition of brain MAO-A, but not MAO-B, by SR 95191 was time dependent, with a 19-fold decrease in the IC50 values being observed over a 30-min incubation period (140 to 7.5 microM). At this time, the SR 95191-induced inhibition of MAO-A was not removed by repeated washings. When the reaction was started by adding the homogenate without prior preincubation with SR 95191, the inhibition of brain MAO-A was fully competitive (Ki = 68 microM).(ABSTRACT TRUNCATED AT 250 WORDS) more...

The inhibiton of type A and B MAO in rat forebrain crude membrane preparation by MD780515, (3-(4-[(3-cyanophenyl)methoxy]phenyl)-5-(methoxymethyl)-2-oxazolidinone-Centre de Recherche Delalande, France) has been investigated in vitro with 5-hydroxytryptamine and beta-phenylethylamine as substrates. The inhibition of the high-affinity binding of [3H]harmaline, a specific marker of type A MAO, was also studied. In the experimental conditions used, MD780515 appeared to be a pure mixed MAO inhibitor (MAOI) of 5-HT deamination, both Km and Vmax being altered [Ki (Dixon) = Ki, (slope) = 2 nM; Ki (intercept) = 12 nM]. Phenylethylamine oxidation could be considered to be noncompetitively inhibited by MD780515 (Ki (slope) = 78 nM; Ki (intercept) = 103 nM). Dixon and intercept replots were hyperbolic, suggesting that, at high concentrations, PEA could be deaminated by both forms of MAO. This hypothesis was confirmed by biphasic inhibition curves of 80 microM-PEA obtained when MD780515, clorgyline, harmaline and deprenyl were used at MAOIs. MD780515 was a potent inhibitor (IC50 = 1-2 nM) of [3H]harmaline binding. Comparatively, clorgyline, 'cold' harmaline and Lilly 51641 inhibited 3H ligand binding, with IC50 of 5, 7 and 40 nM respectively. In conclusion, MD780515 is a reversible, specific and potent type A MAOI. more...

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenylpyridazine] is a novel psychotropic drug which possesses the pharmacological properties of a selective, reversible type A monoamine oxidase inhibitor (MAOI). The MAOI activity of SR 95191 was examined in the rat brain, liver and duodenum and compared to that of clorgyline, harmaline, l-deprenyl, moclobemide and cimoxatone. In vitro, SR 95191 selectively inhibited MAO-A and was less potent than cimoxatone, clorgyline and harmaline, but was more potent than moclobemide. Ex vivo, SR 95191 also preferentially inhibited MAO-A in the brain and was 6 and 13 times less potent than cimoxatone and moclobemide, respectively. Like all MAO-A inhibitors, SR 95191 in vivo caused a dose-dependent increase in striatal 3-methoxytyramine, dopamine, serotonin and in hypothalamic norepinephrine contents. A concomitant decrease in deaminated metabolites was observed. SR 95191 inhibited peripheral MAO activity in liver and duodenum. In brain, liver and duodenum, MAO inhibition induced by SR 95191 was short-lasting. Repeated dosing for 14 days did not enhance MAO-A inhibition. Like all reversible MAOIs, SR 95191 antagonized the long-lasting MAO-A inhibition induced by clorgyline. Finally, SR 95191 did not affect monoamine uptake either in vitro or in vivo and did not interact in vitro with a variety of neurotransmitter or drug receptor sites. Based on these results it is postulated that SR 95191 is a selective and reversible type A MAOI of medium potency, which may be of therapeutic benefit in depressed patients. more...

The cholinomimetic activities of the antidepressant drug minaprine have been investigated, in vitro and in vivo, in rodents. Minaprine, and its metabolite SR 95070B [3-(2-morpholinoethylamino)-4-methyl-6-(2-hydroxyphenyl) pyridazine hydrochloride] selectively displaced [3H]-pirenzepine from its cortical and hippocampal binding sites, and only weakly inhibited the binding of [3H]-N-methylscopolamine in either the rat cerebellum, heart and salivary glands, or the guinea-pig ileum. In mice, none of these drugs induced the typical cholinergic side-effects up to lethal doses. Minaprine and SR 95070B antagonized rotations induced by an intrastriatal injection of pirenzepine in mice, after intraperitoneal and/or oral administration. Minaprine also antagonized atropine-induced mydriasis in mice. Both minaprine and SR 95070B potentiated the tremorigenic effect of oxotremorine without inducing tremor when injected alone. Finally, minaprine and SR 95070B, after parenteral and/or oral injection, antagonized the scopolamine-induced deficit in passive avoidance learning, and enhanced short-term retention in the social memory test, in rats. The muscarinic agonists arecoline, oxotremorine and RS 86 [2-ethyl-8-methyl-2,8 diazaspiro-4,5 decan-1,3 dion hydrobromide], as well as the acetylcholine esterase inhibitors physostigmine and tacrine were active in most of these models. These results indicate that minaprine, and its metabolite SR 95070B, have cholinomimetic activities which could be, at least in part, mediated by their selective affinity for M1 muscarinic receptors. Thus minaprine could represent a potential useful drug for the treatment of senile dementias and cognitive impairments occurring in elderly people. more...

The antidepressant minaprine (3-(2-morpholino-ethylamino) 4-methyl 6-phenyl pyridazine, dihydrochloride) and its main metabolites were examined for their monoamine oxidase (MAO) inhibitory effects in the rat. In our experimental conditions, minaprine displayed in vitro a very weak affinity for brain MAO A and B with IC50S close to 1 mM. However, ex vivo, after intraperitoneal administration, this drug behaved as a specific and short-acting type A MAO inhibitor (MAOI) of mild potency (ED50 = 12.8 mg/kg). In comparison, the reversible type A MAOIs, moclobemide and cimoxatone, were respectively 14 and 15 times more potent. When administered orally, minaprine proved to be considerably less active. The results presented in this study suggest that minaprine inhibits MAO A mainly after being converted into active metabolites. However, the chloroform extractable metabolites were found inactive in vitro towards this enzyme, suggesting that MAO inhibitory activity is mediated by one or more other non-identified metabolites. more...

Minaprine is a new psychotropic drug which has recently proved to be effective in the treatment of various depressive states. In rodents, minaprine exhibits an atypical spectrum of antidepressant and dopaminomimetic activities. Thus in mice minaprine antagonizes the effects of reserpine, decreases immobility time in the behavioural despair test and potentiates the effects of 5-HTP; in rats it antagonizes muricidal behaviour (blocked by PCPA or raphectomy). However, minaprine does not affect yohimbine lethality and does not induce anticholinergic effects in mice. Minaprine also activates central dopaminergic transmission. Thus at low doses the drug antagonizes neuroleptic-induced catalepsy and induces stereotypies in rats. These stereotypies are blocked by neuroleptics. In addition, minaprine (like apomorphine) induces contralateral turning in mice with a unilateral lesion of the striatum, whereas d-amphetamine induces ipsilateral rotations. Unlike classical dopaminomimetic drugs, minaprine does not stimulate locomotor activity in rats. The mechanisms by which minaprine exerts its effects are still unclear, since in vitro minaprine does not affect monoamine uptake or release and does not interact with monoamine receptors. In vivo, minaprine (acute doses) increases 5-HT, decreases 5-HIAA levels in various brain areas and weakly and reversibly inhibits type A MAO; subacute treatments lead to a decrease in the number of 5-HT1 and 5-HT2 receptors. In addition, in the striatum the drug decreases HVA and DOPAC, and increases 3-MT levels, without affecting DA levels. Minaprine also weakly displaces (3H)-spiperone from striatal D2 receptors and increases striatal ACh levels. Finally, minaprine fails to affect brain NA or MHPG levels in acute doses and does not modify beta receptor density in subacute treatment. Thus minaprine appears to be a chemically and pharmacologically original antidepressant drug which activates both 5-HT- and DA-mediated transmission but which is devoid of NAergic and anticholinergic effects. This latter statement is confirmed by the good cardiovascular tolerance of minaprine in dog, monkey and humans, and by the lack of "tricyclic-like" anticholinergic side-effects in man. more...

The behavioural effects of CM 30366, an aminopyridazine derivative, on dopamine-mediated neurotransmissions, have been studied in mice and rats. CM 30366 induced stereotyped behaviour and antagonized haloperidol-induced catalepsy in rats, after parenteral and oral administration. In 6-hydroxy dopamine (6-OHDA)-lesioned mice, CM 30366 induced contralateral rotations and, when injected before 6-OHDA, protected mice against its neurotoxicity. CM 30366 also provoked contralateral rotations when injected directly into the mouse right striatum. After parenteral injection, CM 30366 slightly increased motility in mice, at least at low doses. The stereotypies and rotations (after intrastriatal injection) induced by CM 30366 were antagonized by haloperidol, alpha-methyl-p-tyrosine and reserpine. The effects of CM 30366 were compared to those of direct and indirect dopamine-like drugs. Bromocriptine induced a behavioural profile, which in most aspects, was qualitatively and quantitatively similar to that of CM 30366. Apomorphine was found slightly more potent than CM 30366, but in contrast to the latter, apomorphine-induced stereotypies were insensitive to alpha-methyl-p-tyrosine or reserpine. (+)-Amphetamine and nomifensine were less potent than CM 30366, and unlike CM 30366, induced ipsilateral rotations in 6-OHDA-lesioned mice. These results indicate that CM 30366 is a potent atypical dopamine-like drug of potential therapeutic usefulness. more...

Minaprine (MIN) is a 3-amino-pyridazine derivative which exhibits a profile of psychotropic activities which resembles that of antidepressant drugs as well as that of several dopaminomimetic drugs. This spectrum of activity differs from those observed in the same conditions for tricyclic (imipramine, clomipramine) and atypical (indalpine, nomifensine, amineptine, mianserin) antidepressant drugs. It must be noted that MIN is devoid of anticholinergic and motor stimulant effects. In addition, MIN induces behavioural effects predictive of a dopaminergic stimulation; the profile of this activity differs from that of apomorphine, as well as from those of amphetamine and nomifensine, but somewhat resembles that of bromocryptine. MIN does not induce neuroleptic, anxiolytic or anticonvulsant activities in rodents. These data suggest that MIN is an atypical antidepressant drug which activates both serotonergic and dopaminergic neurotransmissions, by as yet not clearly identified mechanisms. more...

The effects of 1-methyl-4-phenyl - 1,2,3,6-tetrahydropyridine (MPTP) on immune parameters, and the restorative influence of sodium diethyldithiocarbamate (DTC) or deprenyl were evaluated in mice. The concentrations of dopamine (DA), 3-methoxytyramine (3-MT), 3-4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA), were concomitantly measured in the striatum. MPTP depressed T-cell responses. DTC restored these responses as well as the concentration of striatal DA. Deprenyl had no effect on the concentrations of DA and its metabolites, yet it modified the immune responses alike MPTP. The findings suggest a dopamine pathway could be involved in the brain-controlled immunostimulation afforded by DTC. more...

Minaprine (3-[2-morpholino-ethlamino]-4-methyl-6-phenyl-pyridazine dihydrochloride; 30038CM; trade name in France: Cantor) is a new psychotropic drug. The therapeutic profile of minaprine differs from that of other known psychotropic agents; in man the drug antagonizes the "inhibitory syndrome" characterized by decreased spontaneous activity, reduction in basic drives, slowed thoughts, feelings of tiredness and social withdrawal. Preliminary clinical trials have indicated that minaprine may also be effective in certain depressive states. This finding prompted us to study the effects of minaprine in animal models for depression. Like most antidepressants minaprine antagonizes behavioral despair, but the effect exhibits a slow onset and maximal activity is reached 24 h after administration. Minaprine also antagonizes reserpine-induced ptosis, this effect has a rapid onset, and is long-lasting. In contrast, minaprine poorly antagonizes reserpine-induced hypothermia. Unlike most antidepressants minaprine does not potentiate yohimbine-induced lethality. Minaprine potently antagonizes prochlorperazine-induced catalepsy in rats and potentiates amphetamine-induced stereotyped behavior, suggesting that the drug may enhance dopaminergic transmission. Finally, minaprine does not antagonize either oxotremorine-induced tremors or physiostigmine-induced lethality. Taken together the results of the present study indicate that minaprine is active on certain, but not all, animal models for depression and suggest the drug may have a potential clinical utility in the treatment of human depressions. more...

In order to design a selective M1 muscarinic agonist, we synthesized SR 95639A (morpholinoethylamino-3-benzocyclohepta-(5,6-c)-pyridazine, dihydrochloride), a semi-rigid analogue of the aminopyridazine antidepressant drug minaprine. SR 95639A displaced [3H]pirenzepine from its binding sites in rat hippocampal membranes with an IC50 value of 0.27 microM. It only weakly displaced [3H]N-methylscopolamine from cerebellar, cardiac and ileal membranes (10-48 microM), and, up to 100 microM, did not interact with the main other receptors of the rat brain. In rat isolated sympathetic ganglia, SR 95639A induced dose-dependent depolarizations which were antagonized by pirenzepine, and dose dependently suppressed the M current. These latter effects were also pirenzepine-sensitive. After i.p. or oral treatment in mice, SR 95639A never induced the classical cholinergic syndrome, up to lethal doses. Finally, SR 95639A (i.p. and p.o.) antagonized contralateral rotations induced by intrastriatal injection of pirenzepine, in mice. These results suggest that SR 95639A is a selective agonist at central muscarinic M1 receptors and may represent a useful tool for further characterization of the nature and function of muscarinic receptor subtypes. more...

Daily changes in tryptophan-5-hydroxylase (TrH) activity have been studied in six different 5-HT-containing cell groups (B3, B4, B5, B6, B7, B8,) in the brain stem of rats maintained in a regular cycle of 12 h of light and 12 h of darkness. Significant circadian alternations of TrH activity were observed in most of the raphe nuclei tested, although the changes were not identical from one structure to another. The striatum showed daily variations in TrH activity in opposite phase to the nucleus raphe dorsalis which projects specific terminals into this area. Monoamine oxidase (MAO) activity was simultaneously estimated in these nuclei but did not exhibit and significant rhythm, suggesting a specific regulation of TrH. Total protein levels were also subject to daily changes. more...

Rats submitted to regular 12 h cycles of light and darkness for three weeks were sacrificed at various times of the day. 5-HT, 5-HIAA and tryptophan levels were estimated in the fronto-parietal cerebral cortex. Tyrosine and free and total tryptophan levels in serum were estimated in parallel. Significant circadian variations in 5-HT and 5-HIAA levels were found in cerebral tissues. The peaks of 5-HIAA levels were dectected during the lignt and dark periods respectively, the maximal fluctuations being seen between 17.00 h and 21.00 h, two times separating the light off. Important significant circadian variations in free and total serum tryptophan levels were also observed. In both cases, the maximal levels were found during the middle of the dark phase after the peak of 5-HIAA levels. The circadian rhythm of tyrosine levels in serum was in opposite phase with that of tryptophan (free or total). The diurnal changes in tryptophan content in cerebral tissues seemed thus related to those found in serum. Taking in consideration results obtained in previous studies 16,17 carried out in similar experimental conditions, it was concluded that the parallel increase in serum free tryptophan and in tissues 5-HIAA levels seen during the night were not related to a stimulation of 5-HT turnover. Indeed 5-HT synthesis is minimal at this time16. more...

SR 95191 [3-(2-morpholino-ethyl-amino)-4-cyano-6-phenyl-pyridazine], a novel compound, has been shown in preliminary experiments to inhibit type A monoamine oxidase (MAO). This report describes the activities of SR 95191 in behavioral experiments in mice and rats and shows that SR 95191 has the profile of a selective type A MAO inhibitor (MAOI). Moreover, SR 95191 also possesses dopamine (DA) stimulant properties. The activities of SR 95191 were compared to those of the MAOIs moclobemide, clorgyline, pargyline and l-deprenyl, as well as to those of the antidepressant drugs imipramine, nomifensine and indalpine and to those of the DAergic drugs (+)-amphetamine and apomorphine. SR 95191 p.o. antagonized the effects of reserpine in mice and rats, decreased immobility in the mouse despair test, antagonized haloperidol-induced catalepsy in rats and potentiated 5-hydroxytryptophan in mice and rats with an overall potency which was half that of imipramine. SR 95191, like moclobemide, did not potentiate yohimbine-induced lethality and did not antagonize oxotremorine-induced tremor. Like selective type A MAOIs, SR 95191 potentiated 5-hydroxytryptophan-induced tremor without affecting beta-phenethylamine-induced stereotypies in mice. SR 95191 did not antagonize 3-hydroxy-4-methyl-alpha-phenylethylamine-induced hyperthermia. Like all DA stimulant drugs, SR 95191 induced stereotypies in rats, which were blocked by haloperidol and alpha-methylparatyrosine, and induced contralateral turning in mice with a unilateral striatal 6-hydroxydopamine lesion. Based on these results, it is postulated that SR 95191 has a unique profile of activity combining the properties of a selective type A MAO inhibitor and those of an atypical DAergic drug. more...

Rats were administered toloxatone 100 mg kg-1 p.o., and killed 0.5 to 8 hours later. Toloxatone reversibly inhibited type A MAO, but did not affect the activity of type B MAO in whole brain. Cerebral concentrations of noradrenaline, dopamine and 5-hydroxytryptamine were increased after toloxatone, while their metabolite concentrations were reduced. Synaptosomal uptake processes of these amines were not altered by tolaxatone. more...

Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring. more...