PurposeAnti-inflammatory activity of an antiglaucoma drug may be an advantage for long-term treatment of glaucoma since it may reduce the risk of treatment-related inflammatory processes in outer compartments of the eye and probably also prevent or delay progression of glaucomatous retinal neurodegeneration. In this study, the effect of GLC756, a novel mixed dopamine D2 receptor agonist and dopamine D1 receptor antagonist, and timolol on endotoxin-induced cytokine tumor necrosis factor-α (TNF-α) release in serum was examined.MethodsFor endotoxin-induced TNF-α release, 8-week-old Lewis rats were intravenously injected with 160 μg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone were either systemically (1 mg/kg SC for 5 days) or topically (0.4%, 0.5%, and 0.1%, respectively, 20 μL eye drops given 16 times over 48 hours in left and right eye) administered. TNF-α was measured in serum 2 and 48 hours after LPS induction.ResultsA marked TNF-α increase in serum was found 2 hours after LPS induction. Administration of GLC756 and betamethasone, systemically and topically, decreased TNF-α release. However, due to large scattering of mean values only the effect of systemically administered GLC756 was statistically significant. In contrast, timolol increased TNF-α values stronger than LPS alone.ConclusionsThe significant suppression of LPS-induced TNF-α increase by GLC756 suggests an additional anti-inflammatory potential of the dopaminergic compound in the treatment of glaucoma.

Purpose Proliferation of subconjunctival fibroblasts plays a critical role in scarring and failure of glaucoma filtering surgery. Long-term topical glaucoma medications appear to increase fibroblast proliferation. In this study, the effects of topical antiglaucoma drugs latanoprost and GLC756, a novel dopamine D2 agonist and D1 antagonist, on cultured normal human dermal fibroblasts (NHDF) were examined. Methods The NHDF cell line was incubated with latanoprost, prostaglandinF2α (PGF2α), GLC756, or 5-fluorouracil as a positive control at concentrations of 3 and 30 μM for 6, 18, and 24 hours. Fibroblast growth was measured by 5-bromodeoxyuridine (BrdU) uptake using laser scanning cytometry. Results Latanoprost and PGF2α had a biphasic response on the number of cultured NHDF positively stained with BrdU. A stimulating effect on proliferation occurred early, 6 hours after incubation, and an inhibitory effect 18 to 24 hours after incubation. GLC756, in contrast, revealed only inhibitory effects on BrdU uptake 18 to 24 hours after incubation. The pattern of GLC756 was similar to that of the positive control 5-fluorouracil. Conclusions Latanoprost seemed to have a biphasic response on the proliferation of cultured NHDF. First there was a stimulating thereafter a secondary negative modulating effect. GLC756 had a fully antiproliferative effect on the NHDF, indicating an additional potential of novel dopamine compounds for topical glaucoma medication.

Anti-glaucoma drugs exhibiting anti-inflammatory properties are desirable for the long-term treatment of glaucoma since they may reduce the risk for treatment-related inflammatory processes in outer compartments of the eye. The purpose of this study was to evaluate potential anti-inflammatory effects of two topically and systemically applied anti-glaucoma drugs i.e. GLC 756, a novel mixed dopamine D2 receptor agonist and D1 receptor antagonist, and timolol a beta-adrenoceptor antagonist using endotoxin-induced uveitis (EIU) and arthritis in rats as an in vivo model. For EIU, 8-week-old Lewis rats were intravenously injected at 160 microg lipopolysaccharide (LPS) from Salmonella typhimurium. GLC756, timolol, or betamethasone, as a positive control, were either topically (0.4%, 0.5%, and 0.1%, respectively, 16-times 20 microL eye drops during 48 h) or systemically (1mg/kg subcutaneous for 5 days) administered. Cell infiltration in tissue of the eye and knee joint were assessed histopathologically and in special compartments of the eye by confocal microscopy 48 h after LPS-induction. Numerous infiltrating cells were detected in the eyes after LPS-induction and half of the animals showed arthritis. Topical and systemic pre-treatment with GLC756 and timolol resulted in reduced cell infiltration in the eye. In addition, GLC756 reduced, whereas timolol increased the incidence of arthritis. Betamethasone suppressed almost completely the cell infiltration in the eye and the incidence of arthritis. In conclusion, the observations that GLC756 reduced cell infiltration in the eye and the incidence of arthritis after LPS-induction is compatible with anti-inflammatory properties of this drug. By contrast, timolol produced no consistent anti-inflammatory effect since both inhibitory as well as stimulatory effects on inflammatory processes were seen.

[3H]205–501, a noncatechol dopaminergic agonist, is presented as a ligand with high affinity (KD ∼ 1 nM) and high selectivity for dopamine receptors. pKi values of dopaminergic agonists derived from competition isotherms in the [3H]205–501 binding assay correlate very well with their potency in the acetylcholine release assay, which is controlled by dopamine D2 receptors. There is however no correlation with their potency stimulating adenylate cyclase, a process controlled by dopamine D1 receptors. Thus [3H]205–501 is the first agonist ligand selective for dopamine D2 receptors.

The dopamine D4 receptor has lately attracted interest since it has been hypothesized to be involved in the pathogenesis and pharmacotherapy of neuropsychiatric diseases. The present study provides first in vivo evidence of dopamine D4 receptors in primate brain using a [11C]benzo[g]quinoline, the novel radioligand [11C]SDZ GLC 756 ([11C]GLC: in vitro dissociation constants at human receptor clones [nM]: 1.10 at D1; 0.40 at D2; 25 at D3; 0.18 at D4.2; 6.03 at D5). Dynamic positron emission tomography scans were performed on healthy baboons (Papio hamadryas, n = 3). Specific receptor binding (SB) was calculated for striatum and neocortex (frontal, temporal, parietal, and occipital) based on the differences between the regional and the cerebellar concentration of [11C]. Blockade of D1 and D5 receptors by SCH23390 (1.7 pmol/kg) diminished SB in the striatum by 55 +/- 4% (mean +/- standard deviation, P < 0.05) and in the frontal cortex by 13 +/- 8% (P < 0.05) when compared to SB in the unblocked state (SB(D1-D5)). In the presence of the dopamine antagonists SCH23390 (1.7 micromol/kg) and raclopride (5.7 pmol/kg)--which mask the D1, D2, D3, and D5 subtypes--SB of [11C]GLC to D4 receptors (SB(D4)) was demonstrated in the striatum and all cortical regions of interest. In the striatum, the ratio of SB(D4)/SB(D1-D5) was 0.13 +/- 0.07. In the neocortex, SB(D4)/SB(D1-D5) was notably higher (0.77 +/- 0.29; mean of all cortical regions of interest). The widespread distribution of dopamine D4 receptors suggests a basic functional role of this receptor subtype in the modulation of cortical and subcortical neuronal activity.

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Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia. Synapse 25:137–146, 1997. © 1997 Wiley-Liss, Inc.

This investigation was designed as a randomized, placebo-controlled, double-masked, crossover study in NZW rabbits with normal intraocular pressure (IOP) to investigate dopaminergic effects on IOP. SKF 38393, a selective D1-receptor agonist, increased, and SDZ PSD-958, a selective D1-receptor antagonist, decreased IOP, respectively. The selective D2-receptor agonist quinpirole decreased IOP, whereas the selective D2 receptor antagonist metoclopramide had no significant effect. Combinations of quinpirole with SDZ PSD-958 decreased IOP in an additive manner. SDZ GLC-756, a mixed D1-receptor antagonist/D2-receptor agonist, decreased IOP in a dose-dependent manner with a maximum effect greater than the maximum effects produced either by the D1-receptor antagonist SDZ PSD-958 and the D2-receptor agonist quinpirole. The effect of SDZ GLC-756 could only be partially blocked by the selective D2-receptor antagonist metoclopramide suggesting that both D1-receptor blockade and D2-receptor stimulation participate in its IOP-lowering effect. Tonography suggests that SDZ GLC-756 has no significant effect on outflow facility. Furthermore, the results suggest that both D1 and D2 receptors each play an independent role in the regulation of IOP in rabbits. Thus, simultaneous blockade of D1 receptors and stimulation of D2 receptors may provide a new pharmacological approach for the treatment of ocular hypertension frequently associated with glaucoma.

This investigation was carried out to evaluate the effect of SDZ GLC-756, a novel dopamine D-1 antagonist and D-2 agonist, on intraocular pressure (IOP) in rabbits. A randomized, placebo-controlled, double-masked, crossover study with topical application of SDZ GLC-756 eyedrops [0.015% (n = 10), 0.03% (n = 10), 0.0625% (n = 10), 0.125% (n = 9), 0.25% (n = 10), 0.5% (n = 14)] and vehicle alone (placebo-control) to the right eye was performed in New Zealand White rabbits. The contralateral eye received no treatment. IOP was measured using a pneumatonometer. Topical SDZ GLC-756 significantly lowered IOP in a dose-dependent manner (maximal IOP-lowering effect 1 approximately 2 hours after administration) in the treated eye and, to a lesser extent, in the contralateral eye. The duration of action was approximately 4 hours. The simultaneous D-1 antagonistic and D-2 agonistic properties of SDZ GLC-756 may provide a new pharmacological approach to the treatment of glaucoma, which deserves further investigation.

SDZ GLC-756, a novel octahydrobenzo[g]quinoline derivative, is equipotent in displacing [3H]SCH23390 from dopamine D1 receptors and [3H]205–501 from dopamine D2 receptor binding sites. It blocks dopamine sensitive adenylate cyclase with the same potency as SCH23390, indicating antagonist properties at dopamine D1 receptors. On the other hand, SDZ GLC 756 inhibits electrically evoked acetylcholine release from rat striatal slices with the same potency as the selective dopamine D2 receptor agonist bromocriptine. This effect is blocked by spiperone suggesting that it is mediated by dopamine D2 receptor activation. The opposing action of SDZ GLC 756 on dopamine D1 and D2 receptors is also evident in vivo. SDZ GLC 756, like SCH23390, blocks apomorphine-induced rearing in mice. On the other hand, it inhibits prolactin secretion and produces circling in unilateral 6-OHDA-lesioned rats, which is compatible with stimulant properties at dopamine D2 receptors. This drug might be a new tool to study linkage between dopamine D1 and D2 receptors.

SDZ PSD 958, a novel benzo[g]quinoxaline derivative exhibits the properties of a potent orally active selective D1 receptor antagonist. It has high affinity for D1-like receptors (D1, D5; pKi=9.7–9.8) labelled by [3H]SCH23390 and is at least 400 fold less active at D2-like receptors (i.e. D2, D4) labelled by [3H]spiperone. Effects in functional tests are consistent with d1 receptor antagonist properties. SDZ PSD 958 inhibited apomorphine-induced rearing in mice and prevented prolongation of novelty-induced locomotion in rats elicited by the selective D1 receptor agonist CY 208-243. By contrast, SDZ PSD 958 did not induce catalepsy and only weakly inhibited apomorphine-induced stereotyped gnawing in rats. This suggests that SDZ PSD 958 preferentially inhibits responses mediated by dopamine systems innervating the limbic system.

1. Eleven monkeys were administered N-methyl-C-phenyl-1,2,3,6-tetrahydropyridine (MPTP): eight were treated with bromocriptine for one week and then CY 208-243 (four monkeys) or saline (four monkeys) was added to the bromocriptine treatment.2. Addition of CY 208-243 increased the therapeutic response observed with the ergot alone without inducing dyskinesia.3. Following MPTP, [H-3]-SCH 23390 specific binding to D-1 receptors as well as [H-3]-spiperone and [H-3]-N-n-propylnorapomorphine specific binding to D-2 receptors increased in posterior striatum compared to control animals, whereas [H-3]-SKF 38393 binding to D1 receptors tended to decrease.4. Dopamine receptor density was unchanged in anterior striatum of untreated MPTP-monkeys.5. In the posterior striatum, both dopaminergic treatments decreased towards control values [H-3]-SCH 23390, [H-3]-spiperone and [H-3]-N-n-propylnorapomorphine binding whereas they did not significantly change [H-3]-SKF 38393 specific binding. [H-3]-SKF 38393 specific binding increased in anterior striatum of bromocriptine-treated MPTP-monkeys, compared to untreated MPTP-animals, and this increase was abolished in animals treated with bromocriptine + CY 208-243.6. The present study shows that in MPTP-monkeys, treated or not with DA agonists,the D1 and D2 receptor changes are concentrated in the posterior striatum and that denervation appears to cause a shift from the high to the low affinity agonist state of D1 receptors but not for the D2 subtype.