D2 receptor genes--the cause or consequence of substance abuse?
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Animals↗
Biomedical subjects
R E Chipkin
Publications and source records attributed to R E Chipkin.
Effect of SCH 39166, a novel dopamine D1 receptor antagonist, on [3H]acetylcholine release in rat striatal slices.
SCH 39166 is a novel and selective dopamine D1 receptor antagonist. It has been reported to have potential antipsychotic properties and reduced extrapyramidal side-effect liabilities (EPS). The current studies investigated the pharmacological effects of SCH 39166 on striatal cholinergic function in order to further characterize its dopamine D1 receptor selectivity and to address its EPS liability. Electrically stimulated [3H]acetylcholine (ACh) release from rat striatal slices was measured and comparisons were made between SCH 39166, SCH 23390, (-)-sulpiride, haloperidol or apomorphine on their effect on [3H]ACh release. Results indicated that apomorphine inhibited [3H]ACh release from striatal slices (IC50 = 0.31 microM). (-)-Sulpiride and haloperidol completely reversed the inhibition of [3H]ACh release seen with apomorphine. In contrast, SCH 39166, as well as, SCH 23390 did not reverse the inhibition of [3H]ACh release induced by apomorphine. These findings indicate that dopamine D2 receptors are primarily involved in modulation of [3H]ACh release. Furthermore, selective dopamine D1 receptor antagonists, such as SCH 39166, are ineffective in modulating striatal [3H]ACh release, suggesting that striatal cholinergic hyperactivity and possibly EPS will not be a consequence of dopamine D1 receptor blockade.
Acetylcholine↗
Selective up-regulation of D-1 dopamine receptors following chronic administration of SCH 39166 in primates.
Caudate, putamen and frontal cortex tissues were obtained from rhesus monkeys that had taken part in a toxicology study required by the Food and Drug Administration. These monkeys had received daily oral treatments of SCH 39166 at three different doses (3, 12 and 48 mg/kg) for three consecutive months. Plasma membranes from the caudate and putamen were analyzed for changes in D-1 and D-2 receptor affinity and number using saturation analyses of 3H-SCH 23390 and 3H-spiperone binding, respectively. Saturation studies were performed on membranes from the frontal cortex using 3H-ketanserin to determine if 5HT2 receptor number or affinity were affected by chronic treatment with SCH 39166. Results indicate a significant, dose-dependent up-regulation of D-1 receptor number in both caudate and putamen, with no changes in either D-2 receptors in the striatal regions or 5HT2 receptors in the frontal cortex. These data, therefore, indicate that SCH 39166 is a selective antagonist at D-1 receptors in the CNS of nonhuman primates.
Animals↗
SCH 39166, a potential antipsychotic drug, does not evoke movement disorders in cebus monkeys.
Subchronic administration of a neuroleptic in cebus monkeys can reliably mimic the abnormal movements produced by these drugs in humans. SCH 39166 is the best candidate to test in this model to determine if selective antagonism at the dopamine D1 receptor is devoid of these side effects. It has superior selectivity for the dopamine D1 site versus several other sites and a significantly longer duration in primates than the prototypical D1 antagonist, SCH 23390. In contrast to haloperidol, weekly administration of SCH 39166 for 14 weeks did not produce abnormal movements but did produce equivalent sedative effects. Thus dopamine D1 antagonists are uniquely different from D2 antagonists with regards to the production of abnormal movements.
Animals↗
Ligand selection for PET studies of D1 dopamine receptors. Relationship between distribution of binding sites and mRNA for DAARPP32 in the human brain.
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Brain↗
Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615.
The analgesic and acute central nervous system (CNS) side effect potential of the enkephalinase inhibitor SCH 32615 (N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenyl-alanine-beta-alanine) were evaluated after IV administration to mice, rats and squirrel monkeys. In mice, SCH 32615 caused dose-related suppression of acetic acid-induced writhing (minimal effective dose, MED = 3 mg/kg IV). In rats, SCH 32615 produced dose-related increases in the response latencies in the yeast inflamed-paw test (MED = 10 mg/kg IV). In squirrel monkeys, using a new hot-water bath tail-flick test, SCH 32615 significantly prolonged the escape latencies (MED = 100 mg/kg IV). These results in primates are the first data showing an analgesic action of an enkephalinase inhibitor in a reflex model of pain. When measured for its CNS side effect potential, SCH 32615 had no significant effects in rats (up to 100 times its analgesically active doses) or in monkeys (up to three times). In the mouse, at doses 100 times its minimal effective dose, SCH 32615 produced brief convulsions; these lasted only a minute, resolved quickly, and did not cause lethality. In contrast, in rats and squirrel monkeys, the standard opioid analgesic morphine produced profound CNS side effects; this was particularly notable in monkeys, in which morphine's maximal analgesic effects were associated with near lethal respiratory depression. These data demonstrate that SCH 32615 produces selective analgesic actions and that its acute side effect liability is less than that seen with a clinically used standard.
Acetates↗
[3H]SCH 39166, a new D1-selective radioligand: in vitro and in vivo binding analyses.
SCH 39166 [(-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]naphtho[2, 1b]azepine] has recently been described as a selective D1 antagonist and has entered clinical trials for the treatment of schizophrenia. The tritiated analogue of this compound, [3H]SCH 39166, has now been synthesized and characterized for its in vitro and in vivo binding profiles. [3H]SCH 39166 binds to D1 receptors in a saturable, high-affinity fashion, with a KD of 0.79 nM. In competition studies, D1-selective antagonists like SCH 23390 displaced the binding of [3H]SCH 39166 with nanomolar affinities, whereas antagonists of other receptors exhibited poor affinity. In vivo, [3H]SCH 39166 bound to receptors in rat striatum in a fashion suggestive of D1 selectivity. Further, when the time course for the binding of [3H]SCH 39166 was compared with the behavioral time course of the unlabeled compound, the two durations of action were virtually indistinguishable. Similar studies were performed for SCH 23390 and its tritiated analogue, but the in vivo binding of this radioligand exhibited a duration of action far greater than the behavioral activity of the unlabeled drug. In concert, these data demonstrate that [3H]SCH 39166 selectively labels D1 receptors in vitro and in vivo, and that this drug is superior for in vivo imaging of the D1 receptor.
Animals↗
Effects of [N-(L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (SCH32615), a neutral endopeptidase (enkephalinase) inhibitor, on levels of enkephalin, encrypted enkephalins and substance P in cerebrospinal fluid and plasma of primates.
In halothane-anesthetized and -ventilated cynomologus macaque monkeys, the effects of administering vehicle (n = 3) or the neutral endopeptidase inhibitor N-[L-(1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine (16 mg/kg, n = 5; or 100 mg/kg, n = 3, intravenously) was examined. Cisternal CSF aliquots were examined by radioimmunoassay: 1) for Met enkephalin; 2) after trypsin and carboxypeptidase B treatment for encrypted enkephalin (X-ENK); 3) for substance P; and 4) for unmetabolized drug. Similar measures were carried out in femoral artery and femoral venous plasma, except that substance P was not assayed. In CSF, prior to drug, low, but measurable levels of enkephalin (61 pg/ml), X-ENK (285 pg/ml) and substance P (16 pg/ml) were observed. Vehicle-injected animals showed no change from baseline levels over a 4-hr sampling period in either plasma or CSF levels. In contrast, following 16 mg/kg, in CSF, there was a significant 9-fold increase in MET and 11-fold increase in X-ENK at 30 min. CSF-substance P levels rose also by a factor of 2, with the peak effect observed at 60 min. All levels displayed a significant reduction by 4 hr. There was no statistical difference between the maximum effects observed with either the 16- or 100-mg/kg dose. Plasma peptide levels of enkephalin and X-ENK were not altered by drug. CSF displayed significant drug levels by 30 min, which were between 0.1 and 1% of levels observed concurrently in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
In vivo binding of SCH 39166: a D-1 selective antagonist.
SCH 39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl- 5H-benzo[d]naphtho-[2,1b]-azepine] has been identified previously as a potent and selective D-1 antagonist. These studies demonstrated that SCH 39166 binds to the D-1 receptor in vitro and inhibits the rat conditioned avoidance response, a test predictive of antipsychotic activity. The current study demonstrates that SCH 39166 inhibits the in vivo binding of [125I]SCH 38840 to D-1 receptors in rat striatal tissue with an ED50 of 11.67 nmol/animal or 0.016 mg/kg s.c. SCH 39166 did not inhibit the in vivo binding of [125I]SCH 38840 to rat frontal cortex, suggesting that, unlike other D-1 antagonists, SCH 39166 was not binding to 5-hydroxytryptamine (5-HT)2 receptors in vivo. The in vivo binding of SCH 39166 to D-2 receptors was studied using [3H]raclopride and demonstrated that SCH 39166 did not bind to D-2 receptors up to doses of 100 mumol/animal or approximately 150 mg/kg s.c. Further studies to determine the in vivo selectivity of SCH 39166 utilized N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) to inactivate selected neurotransmitter receptors. Preadministration of SCH 39166, at doses as low as 0.01 mg/kg s.c., produced a statistically significant protection of D-1 receptors from EEDQ inactivation. SCH 39166 produced a similar protection of 5-HT2 receptors only at the highest dose tested, 10 mg/kg s.c., whereas there was no protection of D-2 sites even at this high dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
D1 antagonist in clinical trial.
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Animals↗
Studies on the effect of SCH-34826 and thiorphan on [Met5]enkephalin levels and release in rat spinal cord.
SCH-34826 and thiorphan are inhibitors of the neutral endopeptidase (NEP; E.C. 3.4.24.11;) that cleaves the opiate peptides [Met5]- and [Leu5]enkephalin at the glycinylphenylalanine bond. These compounds were evaluated for their ability to affect the levels of [Met5]enkephalin-like immunoreactivity (MELI) in the brain and the spinal cord and the release into the extracellular space under resting and K+-evoked conditions. The results showed that oral administration of SCH-34826 (30-100 mg/kg p.o.) or thiorphan (10-30 mg/kg p.o.) had no effect on tissue levels of MELI. In contrast, both agents caused a dose-dependent increase in both the resting and the K+-evoked levels in spinal perfusates, which reached up to 10 times the control values. These data indicate that tissue (presumably intracellular) stores of [Met5]enkephalin are not affected by NEP inhibition and that it is the extracellular effects of the peptide that are potentiated by enzyme blockade. This agrees with the prior results demonstrating that NEP inhibitors require a nociceptive stimulus sufficient to release endogenous stores of [Met5]enkephalins for their actions to be observed.
Analgesics↗
Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol.
The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.
Animals↗
Acute extrapyramidal syndrome in Cebus monkeys: development mediated by dopamine D2 but not D1 receptors.
The present study assessed the role of dopamine D1 and D2 receptors in the production of an extrapyramidal syndrome (EPS) in Cebus apella monkeys. Previous studies have shown the development of EPS in both old and new world monkeys with haloperidol administration. We now report that repeated weekly administration of a selective D1 antagonist, SCH 23390, does not produce this syndrome in cebus monkeys. Cebus monkeys were treated with either vehicle (n = 6), the specific D2 antagonist haloperidol (0.3 mg/kg p.o., n = 9) or the specific D1 antagonist SCH 23390 (10.0 mg/kg p.o., n = 9) once a week for approximately 1 year and behavioral effects were observed and scored. The drug doses used in this study produced similar sedative scores when given acutely and sedation increased over the first 12 weeks of the study for both treatment groups. However, by the 12th week of dosing with haloperidol all the monkeys showed a profound EPS characterized by limb extensions, head pushing, tongue protrusions and sometimes severe biting movements. In contrast, none of the SCH 23390-treated monkeys showed any abnormal movements, suggesting D1 antagonists have a low EPS side-effect liability. The profile of the incidence of EPS seen with classical neuroleptic drugs in cebus monkeys and their blockade of EPS by anticholinergic drugs mimics the profile seen in humans. The models presented appear to be predictive of the production of the EPS in humans and could be used to screen neuroleptics for EPS liability. Furthermore, the EPS is probably due to the selective blockade of dopamine D2 receptors with its associated enhancement of cholinergic neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacological and behavioral effects of D1 dopamine antagonists.
This work includes the effects of SCH 23390 and related benzazepines on behavior and attempts to relate these effects to their D1 dopamine antagonist action. Effects on conditioned avoidance responding (CAR) in rats were studied under the same conditions in which in vivo binding of the radioiodinated D1 specific benzazepine 125I-SCH 38840 was measured. It was found that there is very close agreement between the time-course for antagonism of CAR and for in vivo displacement of 125I-SCH 38840 from rat striatum. The effect of SCH 23390 in CAR in monkeys was compared with standard anti-psychotics and although its oral potency was reasonable, its duration was very short (1-2 hours at 5 times its minimal effective dose for statistically significant reduction of avoidance). It is concluded from this and prior work that SCH 23390 and other D1 specific benzazepines inhibit CAR at the same doses that bind to D1 receptors in the CNS and that D1 specific antagonists are behaviorally effective at doses that do not produce D2 receptor effects (e.g. increased plasma prolactin levels, catalepsy).
Animals↗
Effects of D1 and D2 antagonists on basal and apomorphine decreased body temperature in mice and rats.
In these experiments representative selective antagonists at D1 (SCH 23390) and D2 (haloperidol) receptors were studied for their effects on basal and apomorphine decreased body temperature in mice and rats. In mice, SCH 23390 (up to 3 mg/kg SC) neither affected basal body temperature nor blocked apomorphine-induced hypothermia (AIH). On the other hand, haloperidol alone was hypothermic and paradoxically also blocked AIH in mice. In rats, SCH 23390 alone produced hyperthermia; the mechanism by which this occurred is not known. SCH 23390 also blocked AIH in rats. However, the inhibition of AIH only occurred at doses of SCH 23390 that were themselves hyperthermic. Haloperidol did not alter basal body temperature but did block AIH in rats. These data suggest that apomorphine-induced body temperature changes are D2 mediated.
Animals↗
Serotonergic component of SCH 23390: in vitro and in vivo binding analyses.
A series of benzazepines related to SCH 23390 were tested for binding to the 5HT-2 receptor. The compounds tested inhibited the binding of 3H-ketanserin with KI values generally greater than those observed for the D-1 receptor, but less than those for the D-2 receptor. When this serotonergic activity was correlated to the D-1 activity, the resulting coefficient was 0.84, indicating a strong correlation between the two activities. Conversely, the 5HT-2 activity did not show a good correlation with the D-2 activity. To further test the significance of the 5HT-2 binding of the SCH 23390, in vivo binding studies were performed using 125I-SCH 38840 in the frontal cortex, an area containing both D-1 and 5HT-2 receptors. The in vivo binding of 125I-SCH 38840 to frontal cortex exhibited peak levels one hour following subcutaneous administration, similar to the time course previously observed in striatum. The binding was both D-1 and tissue specific. Competition studies with selected standards demonstrated that inhibition of the binding to frontal cortex, in contrast to the inhibition observed in the striatum, exhibited a Hill coefficient less than unity, implying interaction at more than one receptor subtype. When SCH 23390 and ketanserin were administered simultaneously, the inhibition of the in vivo binding of 125I-SCH 38840 to striatum was not different than that observed with SCH 23390, alone. However, the inhibition of binding to frontal cortex was significantly greater than that demonstrated with either SCH 23390 or ketanserin, alone, suggesting that 125I-SCH 38840 was binding to both D-1 and 5HT-2 receptors, in vivo.
Animals↗
Endogenous opioids and pain: status of human studies and new treatment concepts.
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Analgesia↗
Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity.
SCH39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl- 5H-benzo[d]naptho-(2,1-b)azepine] is a benzonaphthazepine that has been evaluated as a selective D1 dopamine receptor antagonist. In vitro, SCH39166 (Ki = 3.6 nM) inhibited the binding of [3H]SCH23390 (a D1 specific compound) and blocked dopamine-stimulated adenylate cyclase (Ki = 9.1 nM); in contrast the Ki for SCH39166 to displace [3H]spiperone (D2) was greater than 1 microM and its Ki vs. [3H]-ketanserin (5-hydroxytryptamine2) binding was greater than 300 nM. In vivo, SCH39166 inhibited both rat and squirrel monkey conditioned avoidance responding (minimal effective dose = 10 and 1.78 mg/kg p.o., respectively) and had a duration of at least 6 hr in both species. In addition, SCH39166 antagonized apomorphine-induced stereotypy in rats (minimal effective dose = 10 mg/kg p.o.). These in vivo actions of SCH39166 are similar to the activity of typical dopamine antagonists. However, in contrast to D2-selective antagonists, SCH39166 failed to increase plasma prolactin levels, did not block apomorphine-induced emesis in the dog and had minimal effects on the striatal levels of homovanillic acid or dihydroxyphenylacetic acid. Furthermore, although immobility was seen after p.o. administration of SCH39166 using the inclined screen test, the drug did not cause catalepsy at doses up to 10 times its minimal effective dose in the rat conditioned avoidance response test. Additionally, SCH39166 inhibited apomorphine-induced climbing at lower doses than it inhibited apomorphine-induced sniffing in mice. The results from these latter two tests suggest that SCH39166 may have a reduced liability to produce extrapyramidal side effects. Therefore, based on this profile of activity, SCH39166 is a selective D1 dopamine receptor antagonist both in vitro and in vivo. Additionally, because this compound is longer acting in the primate than previously available D1 antagonists, it has potential utility as a clinically useful drug.
3,4-Dihydroxyphenylacetic Acid↗