A68930: a potent agonist selective for the dopamine D1 receptor

doi:10.1016/0014-2999(91)90459-4

European Journal of Pharmacology

Volume 199, Issue 2, 25 June 1991, Pages 209-219

https://doi.org/10.1016/0014-2999(91)90459-4 Get rights and content

Abstract

A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HC1, is a potent (EC₅₀, = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D₁ dopamine receptor. In the rat caudate-putamen model of the D₁ dopamine receptor, A68930 is a potent (EC₅₀, = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC₅₀ = 3920 nM) full agonist in a biochemical model of the dopamine D₂ receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D₁ receptor. A68930 also displays weak α₂-agonist activity but the molecule is virtually inactive at the α₁- and β-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged ( > 20 h) contralateral turning that is antagonized by dopamine D₁ receptor selective doses of SCH 23390 but not by D₂ receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.

References (38)

G. Al-Tajir et al.
Opposite effects of stimulation of D₁ and D₂ dopamine receptors on the expression of motor seizures in mouse and rat
Neuropharmacology
(1990)
G. Al-Tajir et al.
Proconvulsant effect of SKF 38393 mediated by nigral D₁ receptors
European J. Pharmacol.
(1990)
P.H. Andersen et al.
Thienopyridine derivatives identified as the first selective, full efficacy dopamine D₁ receptor agonists
European J. Pharmacol.
(1987)
P. Barone et al.
Dopamine-D₁ receptor modulation of pilocarpine-induced convulsions
Neuroscience
(1990)
M. Beaulieu et al.
N,N-Disubstituted 2-aminotetralines are potent D-2 dopamine receptor agonists
European J. Pharmacol
(1984)
L. Garau et al.
Dopamine receptors: pharmacological and anatomical evidences indicate that two distinct dopamine receptor populations are present in rat striatum
Life Sci.
(1978)
A.A. Grace et al.
Intracellular and extracellular electrophysiology of nigral dopaminergic neurons. L Identification and characterization
Neuroscience
(1983)
D. Hoyer et al.
[¹²⁵I]SCH 23982, a 'selective' D, receptor antagonist, labels with high affinity 5-HTlc sites in pig choroid plexus
European J. Pharmacol.
(1988)
D.J. Kerkman et al.
A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-l receptor
European J. Pharmacol.
(1989)
P.A. Loschmann et al.
Stereoselective reversal of MPTP-induced parkinsonism in the marmoset after dermal application of N-0437
European J. Pharmacol.
(1989)

T.W. Lovenberg et al.

Dihydrexidine, a novel selective high potency full dopamine D, receptor agonist

European J. Pharmacol.

(1989)

E.K. Richfield et al.

Anatomical and affinity state comparisons between dopamine D, and D2 receptors in the rat central nervous system

Neuroscience

(1989)

P.E. Setler et al.

The central effects of a novel dopamine agonist

European J. Pharmacol

(1978)

R.J. Summers et al.

The characteristics of ad:enoceptors in homogenates of human cerebral cortex labeled by [³H]rauwolscine

Life Sci.

(1983)

J.L. Waddington et al.

Drugs acting on brain dopamine receptors: A conceptual re-evaluation five years after the first selective D-1 antagonist

Pharmacol. Ther.

(1989)

R.Y. Wang

Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization

Brain Res. Rev.

(1981)

R.Y. Wang

Dopaminergic neurons in the rat ventral tegmental area. II. Evidence for autoregulation

Brain Res. Rev.

(1981)

J.D. Winkler et al.

Selective down-regulation of D-1 dopamine mediated rotation behavior in supersensitive mice

Neuropharmacology

(1988)

N.R. Zahniser et al.

DSP4-induced noradrenergic lesions increase β-adrenergic receptors and hippocampal electrophysiological responsiveness

Pharmacol. Biochem. Behav.

(1986)

Cited by (78)

Dopaminergic metabolism is affected by intracerebral injection of Tb II-I isolated from Tityus bahiensis scorpion venom
2022, Toxicon: X
Tb II-I isolated from Tityus bahiensis venom causes epileptic-discharges when injected into the hippocampus of rats. The involvement of neurotransmitters in this activity was investigated. Our results demonstrated that Tb II-I increases the concentrations of dopamine metabolite but does not alter other neurotransmitters. Thus, dopaminergic system seems to be partially responsible for the convulsive process. Specific action on particular neurotransmitter can make this toxin a useful tool to better understand the functioning of the system.
Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia
2017, Biological Psychiatry
Citation Excerpt :
Chronologically, the next compounds of importance were A-68930 and A-77636 (Figure 3), two selective D1 agonists from the novel isochroman chemotype (77,78). A-68930 caused seizures (79), but A-77636 has been widely used experimentally because it appeared to have overcome the bioavailability problems of dihydrexidine and had a long duration of action. In murine and primate species, both compounds caused profound antiparkinsonian effects like dihydrexidine (80,81), but both also caused a profound and rapid tolerance (78,82–84).
Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D₁ receptors (D₁R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D₁R stimulation. D₁R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D₁ agonists, e.g., the first full D₁ agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D₁ agonists with better pharmacokinetics, functionally selective D₁ ligands, and D₁R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D₁R stimulation in the dlPFC that can be translated into clinical practice.
Subunit-specific modulation of [<sup>3</sup>H]MK-801 binding to NMDA receptors mediated by dopamine receptor ligands in rodent brain
2012, Neurochemistry International
Citation Excerpt :
As a positive control, we first examined the effect of the non-competitive open channel NMDAR antagonist, memantine (Bormann, 1989), which gave a 72 ± 2% decrease in [3H]MK-801 binding (p < 0.001) (Fig. 2B). The same concentration of the D1R agonists A-68930 and SKF-38393, both of which activate adenylyl cyclase as well as phospholipase C activities (DeNinno et al., 1991; Rosengarten and Friedhoff, 1998; Undie et al., 1994), decreased [3H]MK-801 binding by 56 ± 2% (p < 0.001) and 47 ± 4% (p < 0.001), respectively. Similarly, the D1R agonists dihydrexidine, which also activates adenylyl cyclase (Lovenberg et al., 1989) decreased [3H]MK-801 binding by 49 ± 4% (p < 0.001), and SKF-83822, another activator of adenylyl cyclase (Undie et al., 1994), decreased [3H]MK-801 binding by 50 ± 3% (p < 0.001).
Dopamine D1 receptor (D1R) ligands may directly interact with the NMDA receptor (NMDAR), but detailed knowledge about this effect is lacking. Here we identify D1R ligands that directly modulate NMDARs and examine the contributions of NR2A and NR2B subunits to these interactions. Binding of the open channel blocker [³H]MK-801 in membrane preparations from rat- and mouse brain was used as a biochemical measure of the functional state of the NMDAR channel. We show that both D1R agonist A-68930 and dopamine receptor D2 antagonist haloperidol can decrease [³H]MK-801 binding with increased potency in membranes from the NR2A^–/– mice (i.e. in membranes containing NR2B only), as compared to the inhibition obtained in wild-type membranes. Further, a wide range of D1R agonists such as A-68930, SKF-83959, SKF-83822, SKF-38393 and dihydrexidine were able to decrease [³H]MK-801 binding, all showing half maximal inhibitory concentrations ∼20 μM, and with significant effects occurring at or above 1 μM. With membranes from D1R^–/– mice, we demonstrate that these effects occurred through a D1R-independent mechanism. Our results demonstrate that dopamine receptor ligands can selectively influence NR2B containing NMDARs, and we characterize direct inhibitory NMDAR effects by different D1R ligands.
Dopamine D<inf>1</inf> vs D<inf>5</inf> receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling
2008, Neuropharmacology
Citation Excerpt :
A major finding of the present study is that the characteristic induction of behavioral seizures following challenge with SKF 83822 is abolished in mice with homozygous deletion of the D1 receptor. This finding supports our recent observation that SKF 83822-induced behavioral seizures are conserved in D5 receptor knockouts (O'Sullivan et al., 2005) and, together with numerous reports that the PLC-stimulating SKF 83959 does not induce seizures (Clifford et al., 1999; McNamara et al., 2003; O'Sullivan et al., 2005, 2006), provides strong evidence that the ability of certain D1-like agonists to lower seizure threshold (DeNinno et al., 1991; Starr and Starr, 1993) is critically dependent on selective D1 receptor stimulation of AC-mediated signalling transduction cascades. Unlike other selective D1-like agonists, SKF 83822 induced mildly stereotyped sniffing, locomotion and rearing directed around the perimeter of the cage (thigmotaxis) in wild-type but not D1 knockouts.
Recent reports have shown that the selective dopamine D₁-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D₁ vs D₅ receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D₁, D₅ and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D₁ knockouts. In both heterozygous and homozygous D₅ knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D₁-like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D₁, and to a lesser extent D₅, receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822.
Functional selectivity of dopamine D<inf>1</inf> receptor agonists in regulating the fate of internalized receptors
2007, Neuropharmacology
Citation Excerpt :
The effects of D1 agonists other than dopamine itself on regulatory events downstream of receptor activation are not well characterized. Besides heuristic interest in these questions, several of the D1 agonists that have been tested as antiparkinson agents in human and non-human primates caused a very rapid tolerance evidenced as an almost complete loss of response within a day or so (Asin and Wirtshafter, 1993; Kebabian et al., 1992; Lin et al., 1996; DeNinno et al., 1991a; Johnson et al., 1992). Thus, such molecular events may be important in understanding the cellular mechanisms that contribute to the development of this therapeutic tolerance.
Recently, we demonstrated that D₁ agonists can cause functionally selective effects when the endpoints of receptor internalization and adenylate cyclase activation are compared. The present study was designed to probe the phenomenon of functional selectivity at the D₁ receptor further by testing the hypothesis that structurally dissimilar agonists with efficacies at these endpoints that equal or exceed those of dopamine would differ in ability to influence receptor fate after internalization, a functional endpoint largely unexplored for the D₁ receptor. We selected two novel agonists of therapeutic interest that meet these criteria (the isochroman A-77636, and the isoquinoline dinapsoline), and compared the fates of the D₁ receptor after internalization in response to these two compounds with that of dopamine. We found that dopamine caused the receptor to be rapidly recycled to the cell surface within 1 h of removal. Conversely, A-77636 caused the receptor to be retained intracellularly up to 48 h after agonist removal. Most surprisingly, the D₁ receptor recovered to the cell surface 48 h after removal of dinapsoline. Taken together, these data indicate that these agonists target the D₁ receptor to different intracellular trafficking pathways, demonstrating that the phenomenon of functional selectivity at the D₁ receptor is operative for cellular events that are temporally downstream of immediate receptor activation. We hypothesize that these differential effects result from interactions of the synthetic ligands with aspects of the D₁ receptor that are distal from the ligand binding domain.
The anorectic effect of the selective dopamine D<inf>1</inf>-receptor agonist A-77636 determined by meal pattern analysis in free-feeding rats
2006, European Journal of Pharmacology
Free-feeding rats meet much of their daily energy requirements by consuming food in meals during the nocturnal phase of the night/day cycle. Meal pattern analysis methodology has been developed to record the patterns of meal taken over a 24-h period, and to provide detailed information on a number of meal-related parameters. Previous work indicates that selective dopamine D₁-receptor agonists reduce food intake in short-term feeding tests under the control of homeostatic or hedonic factors. In the present study, our aim was to investigate the effects of the dopamine D₁-receptor agonist, A-77636 (0.1–1.0 mg/kg, s.c.), administered just prior to the start of the night period, on the free-feeding and drinking patterns of rats maintained on a standard ad libitum diet. The results indicate that A-77636 exerted a suppressant effect on food intake, due principally to a reduction in meal size and duration. We conclude that there is a dopamine D₁-receptor involvement in the normal controls of meal size, and that selective D₁-receptor agonists may act to limit meal size.

View all citing articles on Scopus

View full text