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L C Iorio

Publications and source records attributed to L C Iorio.

At least 19 recordsLinked to original sources
PubMed1992

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↗
PubMed1991

Anticholinergic drugs potentiate dopamine D1 but not D2 antagonists on a conditioned avoidance task in rats.

The present study investigated whether blockade of conditioned avoidance responding (CAR) in rats by selective D1 and D2 receptor antagonists could be differentially affected by anticholinergics. The results show that atropine and scopolamine dose-relatedly antagonized the effects on CAR of two specific D2 receptor blockers, haloperidol and raclopride, but potentiated the effects of three specific D1 receptor antagonists, SCH 23390, SCH 39166 and NO-01-0756. Of the less specific dopamine receptor antagonists tested, scopolamine blocked the effects of clozapine and cis-flupenthixol, but did not alter the effects of chlorpromazine, thioridazine or cis-piflutixol. Although the mechanisms involved in the differential shifts by the anticholinergics are unknown, the results are consistent with the view that CAR antagonism by the specific D2 vs. D1 receptor antagonists involves unique and separate mechanisms of action. With respect to the less specific dopamine receptor antagonists, the CAR blockade seen with clozapine and cis-flupenthixol might reflect predominant D2 receptor blockade because their effects were blocked by atropine. In contrast, the CAR blockade by chlorpromazine, thioridazine and cis-piflutixol antagonists might be mediated by equal degrees of D1 and D2 receptor blockade inasmuch as they were not blocked or potentiated by atropine. The antagonism of CAR in rats by the D1 receptor antagonists suggests that these drugs have potential antipsychotic activity in humans. However, they do not appear to enhance central cholinergic transmission and therefore may be devoid of the side effects produced by the antipsychotics in clinical use.

Administration, Oral↗
PubMed1990

Pharmacological evaluation of SCH-12679: evidence for an in vivo antagonism of D1-dopamine receptors.

The benzazepine compound SCH-12679 has been shown to have clinical efficacy against aggressive behavior in mentally deficient patients. The purpose of the present investigation was to evaluate the potential mechanism of action of SCH-12679. Because of the structural similarity of SCH-12679 to compounds influencing D1-dopamine receptors, even though in vitro studies indicated no direct action on this receptor, investigations focused on the possibility that in vivo SCH-12679 antagonizes the function of this dopamine receptor subtype. After i.p. administration to neonatal-6-hydroxydopamine (6-OHDA)-lesioned rats, SCH-12679 reduced, dose-dependently, the locomotor activity induced by SKF-38393, a D1-dopamine agonist. A dose of SCH-12679 that antagonized the activity induced by SKF-38393 in neonatally lesioned rats also blocked various behaviors observed after administration of this D1-dopamine agonist. SCH-12679 did not alter the activity or behavioral responses induced by quinpirole, a D2-dopamine agonist, when administered to 6-OHDA-lesioned rats. SCH-12679 antagonized the self-mutilation behavior and behavioral responses induced by L-dihydroxyphenylalanine in neonatal-6-OHDA lesioned rats in a manner similar to the prototypic D1-dopamine antagonist SCH-23390 and, like SCH-23390, produced a deficit in avoidance responding in unlesioned rats. SCH-12679 produced a small, transient activation of locomotor activity immediately after administration to neonatal-6-OHDA-lesioned rats that was not observed in unlesioned or adult-6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1988

Use of the selective benzodiazepine-1 (BZ-1) ligand [3H]2-oxo-quazepam (SCH 15-725) to localize BZ-1 receptors in the rat brain.

Receptor autoradiographic techniques have been used to localize benzodiazepine-1 (BZ-1) receptor sites by employing a tritiated form of 2-oxo-quazepam (SCH 15-725), a metabolite of the benzodiazepine quazepam (SCH 16-134). Labeling of the receptors was quantitatively determined to be most abundant in areas of the rat brain known through previous autoradiographic studies to bind preferentially with BZ-1 selective ligands. These areas include lamina IV of the parietal cortex, substantia innominata, anterior amygdaloid nucleus, substantia nigra, zona incerta, and molecular layer of the cerebellum. Autoradiographic localization of binding sites for [3H]2-oxo-quazepam provides additional support for the hypothesis that this compound identifies the BZ-1 receptor subtype and demonstrates the utility of this ligand for quantitation of the distribution and density of these sites.

Animals↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

Pharmacology of SCH 34826, an orally active enkephalinase inhibitor analgesic.

SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine] was synthesized as a p.o. active prodrug enkephalinase inhibitor. In vivo, it is de-esterified to SCH 32615 (N-[L-(-1-carboxy-2-phenyl)ethyl]-L-phenylalanyl-beta-alanine), the active constituent. In vitro, the Ki for SCH 32615 to block the degradation of Met5-enkephalin by isolated enkephalinase is 19.5 +/- 0.9 nM. In contrast, SCH 32615 did not inhibit aminopeptidase or diaminopeptidase III degradation of Met5-enkephalin up to 10 microM and did not affect angiotensin converting enzyme up to 10 microM. In vivo, p.o. administered SCH 34826 potentiated the analgesic effects of D-Ala2-Met5-enkephalinamide in mice (ED50 = 5.3 mg/kg p.o.) and rats [minimal effective dose (MED) = 1 mg/kg p.o.]; SCH 32615 had no effect up to 30 mg/kg p.o., but was active parenterally (ED50 in mice = 1.4 ng/kg sc). Direct, naloxone-reversible analgesic effects of SCH 34826 were demonstrated in the mouse low temperature hot-plate test (MED = 30 mg/kg p.o.), the mouse acetic acid-induced writhing test (MED = 30 mg/kg p.o.), the rat stress-induced analgesia test (MED = 10 mg/kg p.o.) and the modified rat yeast-paw test (MED = 100 mg/kg p.o.). Using the rat D-Ala2-Met5-enkephalinamide potentiation test the duration of action of SCH 34826 was at least 4 hs. No respiratory or gastrointestinal side effects of any consequence were noted at doses up to 100 times those active in the D-Ala2-Met-5-enkephalinamide potentiation test.

Administration, Oral↗
PubMed1987

D1 and D2 dopamine binding site up-regulation and apomorphine-induced stereotypy.

Treatments with drugs to up-regulate specific receptors is a strategy often employed in mechanism of action studies. In this type of experiment, changes in the numbers of receptors and concomitant changes in an animal's sensitivity to the drug have been used as evidence for the participation of the binding site in the behavior. In these studies, to test for the role of D1 and D2 receptors in apomorphine-induced stereotypy (AIS), dopamine binding sites were up-regulated by appropriate pre-treatments and the ability of these pre-treatments to alter AIS was subsequently investigated. In the first experiment, 19 days of pre-treatment with SCH 23390 or haloperidol selectively increased by 35 and 40% the numbers of striatal D1 and D2 binding sites, respectively, without affecting their affinities. However, when challenged with apomorphine, only the animals pre-treated with the D2 antagonist showed behavioral supersensitivity. In the second experiment, reserpine pre-treatment (30 mg/kg IP, 24-hr pre-test) increased the numbers of D1 binding sites by 18%, but did not significantly alter the numbers of striatal D2 binding sites. Behaviorally, these rats were supersensitive to apomorphine's stereotypy-inducing effects; however, they also showed an increased sensitivity to the ability of either haloperidol or SCH 23390 to block AIS. Moreover, this blockade was only attenuated by a D2 (but not a D1) agonist. Collectively, these data suggest that AIS is mediated by both D1 and D2 binding sites, but that D2 binding sites have a more important role.

Animals↗
PubMed1987

6-hydroxydopamine treatments enhance behavioral responses to intracerebral microinjection of D1- and D2-dopamine agonists into nucleus accumbens and striatum without changing dopamine antagonist binding.

Behavioral responses to D1 and D2-dopamine agonists are enhanced when these agonists are administered systemically to 6-hydroxydopamine (6-OHDA)-lesioned rats. In the present investigation, microinjection of SKF-38393, a D1-dopamine agonist, into the nucleus accumbens of adult rats lesioned as neonates with 6-OHDA produced a dose-related increase in locomotor activity that was enhanced markedly compared to control. LY-171555, a D2-agonist, elicited less locomotor activity than did SKF-38393 after microinjection into this site. Administration of SKF-38393 or LY-171555 into the nucleus accumbens did not increase locomotion in unlesioned rats at the doses administered to lesioned animals. In adult-6-OHDA-lesioned rats, microinjection of SKF-38393 into the nucleus accumbens also increased locomotion more than did LY-171555. As described previously, systemic administration of SKF-38393 produced little locomotion in adult-6-OHDA-lesioned rats, whereas LY-171555 produced a markedly enhanced response. Administration of SKF-38393 or LY-171555 into the caudate nucleus of neonatally and adult-6-OHDA-lesioned rats produced negligible locomotor activity, but did induce stereotypic behaviors similar to those observed after systemic treatment with these drugs. Stereotypic behaviors occurred to a greater degree in the 6-OHDA-lesioned rats than in unlesioned controls. A regional specificity for certain behaviors induced by dopamine agonist administration was observed. In spite of the enhanced behavioral responses of D1 and D2-dopamine agonists after microinjection into the brain of 6-OHDA-lesioned rats, binding of [3H]spiperone (D2-receptor antagonist ligand) and [3H]SCH 23390 (D1-receptor antagonist ligand) to tissue from striatum and nucleus accumbens was not altered significantly. In contrast to this lack of change in binding characteristics in 6-OHDA-lesioned rats, blockade of dopaminergic transmission with haloperidol treatment caused an elevation of [3H]spiperone binding sites in striatum without affecting affinity for the site. However, chronic haloperidol treatment did not alter significantly [3H]SCH 23390 binding to striatal membranes. These latter findings suggest that chronic dopamine receptor blockade need not produce the same adaptive mechanisms as destruction of dopamine-containing neurons. Thus, a change in receptor characteristics as measured by dopamine antagonist binding does not account for the behavioral supersensitivity observed after D1- and D2-dopamine agonist administration to neonatally or adult-6-OHDA-treated rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1986

Guanine nucleotide regulation of agonist interactions at [3H]SCH23390-labeled D1 dopamine receptors in rat striatum.

We report here the regulation of agonist interactions with [3H]SCH23390-labeled D1 dopamine receptors in rat striatum. Scatchard analyses of [3H]SCH23390 saturation data revealed a single high affinity binding site (KD = 0.49 nM) with a Bmax of 64 pmol/g tissue. The specific binding of 0.25 nM [3H]SCH23390 represented 90% of total binding. Antagonist competition for [3H]SCH23390 binding was monophasic (i.e. pseudo-Hill slope approximately 1) and the rank order of antagonists' affinities was consistent with the pharmacology of D1 dopamine receptors (e.g. cis-flupentixol greater than haloperidol greater than spiperone). In contrast, agonist competition curves were shallow (pseudo-Hill slope less than 1) and computer-assisted analysis indicated that, for all agonists, the data best fit a two-site model composed of a high (KH) and a low (KL) affinity component. In the presence of 0.3 mM GTP, the high affinity binding component (%RH) of various agonists was reduced by approximately 50%. No significant effect of 0.3 mM GTP on [3H]SCH23390 binding was observed. Additionally, it was noted that [3H]SCH23390 labels S2 serotonin receptors in extrastriatal brain regions. However, [3H]SCH23390 apparently does not have an affinity high enough to label S2 receptors at the concentration of [3H]SCH23390 employed in labeling striatal D1 dopamine receptors. These data indicate that [3H]SCH23390 represents a superior radioligand for labeling the two-state striatal D1 dopamine receptor in that its high percent specific binding makes it especially suitable for detailed mechanistic studies of this receptor.

Animals↗
PubMed1986

Interaction studies in mice of SCH 29851, a potential non-sedating antihistamine, with commonly used therapeutic agents.

SCH 29851 was studied for its ability to interact with selected drugs used in man. The non-sedating antihistamine terfenadine and the sedating antihistamine diphenhydramine were also studied for comparison. SCH 29851 at 80 mg/kg po in mice, a dose about 50 times its ED50 for blocking histamine-induced paw edema in the same species, potentiated the anticonvulsant effects of diazepam. At the high dose of 320 mg/kg po, about 80 times its ED50 for antihistamine effects, SCH 29851 potentiated the ability of high doses of ethanol and hexobarbital to induce loss of righting reflexes (LRR). However, no potentiation was seen when SCH 29851 was studied with lower doses of ethanol or phenobarbital that had anticonvulsant effects but did not cause LRR. At this high dose of 320 mg/kg po, SCH 29851 also did not interact with the antihypertensive drugs propranolol and alpha-methyldopa, the anti-ulcer drug cimetidine, the nasal decongestant pseudoephedrine, or the CNS stimulant d-amphetamine. A nearly identical profile of interactions was seen with terfenadine, including potentiation of diazepam at 50 times its antihistamine ED50, potentiation of ethanol- and barbiturate-induced LRR at 80 times its antihistamine ED50, and lack of interaction effects at 320 mg/kg po with each of the other tested drugs. The demonstration in this study of the significant interactions between diphenhydramine and many of the tested drugs is consistent with the clinical experience in man that this drug does have sedating properties and significant interactions with drugs like ethanol and diazepam.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Preclinical evaluation of behavioral deficits following hypnotic drug treatment.

Most hypnotic medications result in performance decrements, or "hangover effects," the morning after bedtime ingestion. However, the severity of hangover effects with new compounds is difficult to predict prior to clinical trials. This paper describes a preclinical procedure that is predictive of human hangover effects following bedtime ingestion of hypnotic medication. Four cebus monkeys were shaped to discriminate between two levers such that rapid responses following the cue light maximized the probability of reinforcement. Subsequently, performance was evaluated one hr (immediate condition) and 8 3/4 hr (delayed condition) after the administration of flurazepam, triazolam, pentobarbital and placebo. All drugs caused dose-dependent performance decrements in both conditions. Significantly higher doses of triazolam were required to impair performance during the delayed condition as compared to the immediate condition, but no such differences occurred with either flurazepam or pentobarbital. These findings parallel human data which indicate that sleep-inducing doses of flurazepam and many barbiturates, but not triazolam, cause performance decrements the morning after bedtime ingestion.

Animals↗
PubMed1985

Pharmacological effects of SCH 30497--a novel analgesic substance.

SCH 30497 (2-[3-(1,2,3,6-tetrahydro-4-2(methylphenyl)-pyridin-1-yl) -propyl]-1,2,4-triazolo[4,3-a] pyridin-3-(2H)-one) was tested for analgesic effects in the rat, mouse and squirrel monkey. SCH 30497 showed dose-related analgesic effects in the rat yeast-paw test; at peak times the ED7sec (95% confidence limits) in mg/kg via the oral, subcutaneous, intramuscular and intravenous routes of administration were as follows, respectively: 4.7 (2.1-9.8), 5.7 (3.4-9.6), 6.4 (4.1-9.8) and 1.4 (0.6-3.2). SCH 30497 was also analgesic in the acetic acid-induced writhing test in mice (ED50 = 1.9 mg/kg p.o.) and the squirrel monkey shock titration test (ED50 = 14.5 mg/kg p.o.). It was inactive in the mouse (100 mg/kg p.o.) and rat (40 mg/kg p.o.) tail-flick tests. Thus, SCH 30497 was efficacious versus chemical, mechanical and electrical nociceptive stimuli. Naloxone antagonism of the analgesic effects of SCH 30497 was species specific with significant inhibition observed only in the rat and not in the mouse or monkey. SCH 30497 did not produce Straub tail or hyperactivity in mice. Twice daily dosing at 30 mg/kg p.o. to rats for 5 days failed to produce tolerance; in separate experiments, daily injections for 10 days at 20 or 100 mg/kg p.o. failed to induce signs of dependence following naloxone challenge. SCH 30497-induced analgesia was not attenuated in rats previously made tolerant to narcotics by implantation of a morphine pellet. SCH 30497 showed a weak ability to displace 3H-Met5-enkephalin from its binding sites on rat brain membranes (IC50 = 48 microM). SCH 30497 (100 microM) did not affect prostaglandin synthesis in vitro. In vivo, the drug did not have anti-inflammatory or ulcerogenic effects up to 80 mg/kg p.o. Acute behavioral, neurological and autonomic side effects were primarily depressant in rodents and occurred at doses greater than 15 times those that were analgesically relevant. Moderate doses in the monkey (2.5 times the ED50) and high doses in mice produced convulsions. It is hypothesized that SCH 30497-like drugs represent a new class of analgesics based on this unique pharmacological spectrum of activity.

Acetates↗
PubMed1983

Determination of analgesic drug efficacies by modification of the Randall and Selitto rat yeast paw test.

This report describes a modified Randall and Selitto (1957) rat yeast paw test that can evaluate differences in efficacy of different analgesics. The modifications consist of a decrease in the rate of acceleration of the noxious stimulus (mechanical pressure) on the inflamed paw from 20 to 12.5 mmHg/sec and an extension of the cut-off time from 15 to 60 sec. All the narcoticlike drugs tested (morphine, codeine, and pentazocine) increased the response latencies of the inflamed paws to the cut-off time. The nonsteroidal antiinflammatory-like drugs tested (acetylsalicylic acid, acetaminophen, indomethacin, phenylbutazone, and proquazone) showed plateaus in their analgesic effects (i.e., increasing the dose failed to produce significantly greater increases in the response latencies compared to the next lower dose). Zomepirac (80-240 mg/kg p.o.) did not show this plateau effect, but was unable to increase response latencies to greater than 30 sec because of the toxicity of higher doses (320 mg/kg p.o.). Flunixin NMG (the meglumine salt of flunixin), a nonnarcotic analgesic, did not display a plateau effect and increased response latencies to maximum values. The methodology was therefore able to discriminate analgesics active against mild to severe clinical pain (narcoticlike) from those only useful against mild to moderate pain (nonnarcotic-like).

Analgesics↗
PubMed1983

SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems.

SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.

Animals↗