SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Metabolic stabilization of benzylidene ketal M(2) muscarinic receptor antagonists via halonaphthoic acid substitution.

The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.

The dopamine D(1) receptor agonist SKF-82958 serves as a discriminative stimulus in the rat.

We examined the discriminative stimulus effects of the high-efficacy dopamine D(1) receptor agonist (+/-)6-chloro-7, 8-dihydroxy-3-ally1-phenyl-2,3,4,5-tetrahydro-1H-3benzazepine++ + hydrobromide (SKF-82958) in rats trained to discriminate SKF-82958 (0.03 mg/kg) from vehicle in a two-lever food-reinforced drug discrimination task. SKF-82958 produced dose-related increases in responding to the SKF-82958 appropriate lever with full substitution occurring at the training dose. Pretreatment with the dopamine D(1)/D(5) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-hexahydro-3-chloro-2hydroxy-N-methyl-5H-benzo-[d]naphtho -¿2, 1-b¿azepine (SCH-39166) (0.01 mg/kg) attenuated the discriminative stimulus effects of SKF-82958. Pretreatment with the dopamine D(2) receptor antagonist raclopride (0.03 mg/kg) had no effect. The high-efficacy dopamine D(1) receptor agonist R(+)6chloro-7, 8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297) fully substituted for SKF-82958, whereas the low-efficacy dopamine D(1) receptor agonist (+/-)1-phenyl-2,3,4, 5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF-38393) produced only partial substitution. The dopamine D(2) receptor agonist trans-(+/-)-4,4a,5,6,7,8,8a, 9-octahydro-5-propyl-1H-propyl-1H-pyrazolo[3,4-g]quinoline dihydrochloride (quinpirole) and the indirect dopamine agonist cocaine did not substitute fully for the SKF-82958 discriminative stimulus cue. These results demonstrate that the high-efficacy dopamine D(1) receptor agonist SKF-82958 can serve as an effective discriminative stimulus in the rat, and that these effects are mediated by a dopamine D(1)-like receptor mechanism.

Benzylidene ketal derivatives as M2 muscarinic receptor antagonists.

Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.

Reduction of dizocilpine and scopolamine-induced deficits in avoidance responding by SCH 54388, a metabolite of felbamate.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel antiepileptic agent with a unique structure and mechanism of action, possibly involving binding sites at the N-methyl-D-aspartate receptor (NMDA) complex. A monocarbomate metabolite of felbamate (SCH 54388) was compared to felbamate using a mouse passive-avoidance paradigm (PAR). SCH 54388 was markedly free of toxic side effects up to doses of 300 mg/kg, sc. SCH 54388 reduced the deficit-producing effects of either scopolamine, a cholinergic antagonist, or dizocilpine (MK-801), an NMDA receptor channel blocker, in a dose-dependent manner. The effective dose range of SCH 54388 was between 0.01 and 10 mg/kg, sc. SCH 54388 was also orally active at doses between 0.1 and 10 mg/kg. Felbamate also reduced scopolamine and dizocilpine antagonism, but was less potent than SCH 54388, reducing scopolamine-induced deficits at 1 to 3 mg/kg, sc. in a dose-dependent manner and reducing deficits induced by dizocilpine at doses of 0.1 and 3 mg/kg, SC. The reduction of dizocilpine-induced deficits by felbamate was not dose dependent. These results suggest that SCH 54388 has a mechanism of action involving either directly or indirectly, glutaminergic and cholinergic central neuronal systems.

Behavioral and physiological effects of xanthines in nonhuman primates.

Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identification of mechanisms that mediate their pharmacological effects has considerable relevance for drug development and therapeutics. Two primary mechanisms involving the cyclic nucleotide system have been implicated as the bases for the effects of xanthines in the CNS. Many xanthines bind to specific adenosine recognition sites and block the actions of adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesterases, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has characterized the behavioral, respiratory and cardiovascular effects of a number of xanthines and related drugs differing in affinity at different subtypes of adenosine receptors and in capacity to inhibit different molecular forms of PDE. The behavioral-stimulant effects of xanthines appear to be mediated principally by their adenosine-antagonist actions and may be limited by PDE inhibition. The respiratory-stimulant and cardiac effects of xanthines, on the other hand, appear to be linked more closely to their PDE-inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A2 and cAMP-specific (possibly type IV) PDE mechanisms play especially prominent roles in mediating the behavioral and physiological effects of xanthines in nonhuman primates.

Cholinergic improvement of a naturally-occurring memory deficit in the young rat.

In a single-trial, passive-avoidance response (PAR) paradigm, young rats at post-natal day (PND) 16 were found to exhibit a performance deficit that diminished progressively with age. When administered prior to training, single peripheral injections of cholinomimetic drugs, either a muscarinic agonist (arecoline, pilocarpine or oxotremorine), an acetylcholinesterase inhibitor (tacrine or E2020), or nicotine, increased the response latencies for young rats to that of adult levels in a dose-dependent manner (overall dose range = 0.003 microgram/kg-10 mg/kg). Neither the cholinergic antagonists scopolamine, atropine or mecamylamine, nor a series of non-cholinergic drugs, diazepam, haloperidol, phenobarbital, pargyline, D-amphetamine, imipramine, piracetam or N-methyl-D-aspartate (NMDA) increased PAR latencies. When 0.1 mg/kg scopolamine was given to young rats prior to arecoline, the dose-effect curve for enhanced latency times was shifted to the right. Higher doses of scopolamine completely blocked the effects of arecoline. Scopolamine (0.001-1.0 mg/kg) administered subsequent to, rather than before PAR training, blocked the usual arecoline-induced enhancement of response latencies. Alternatively, consolidation could be facilitated with different doses of tacrine (0.0003-10 mg/kg). These results demonstrate that young rats fail to remember the PAR but that retention for this task can be specifically enhanced with cholinomimetic drugs.

Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat.

This study tested the hypothesis that blockade of D-1 dopamine receptors in the nucleus accumbens shell, central nucleus of the amygdala or dorsal striatum by intracerebral microinjection of the dopamine antagonist SCH 23390 produces an attenuation of the effects of self-administered cocaine. Microinjection of SCH 23390 (0-4.0 micrograms total dose) into any of the three brain regions dose-dependently increased the rate of cocaine self-administration, consistent with a partial attenuation of the effects of cocaine under these conditions (0.25 mg cocaine i.v.; fixed-ratio 5 timeout 20 s). The regional rank order potency of SCH 23390 was accumbens > amygdala > striatum, striatal injections being equipotent with subcutaneous administration. Moreover, SCH 23390 produced rapid effects on cocaine self-administration only when injected into the accumbens or amygdala. The time course of this regional selectivity was consistent with the rate of diffusion of SCH 23390 from the site of injection as measured by quantitative autoradiography, demonstrating that the regional selectivity of intracerebral injections of SCH 23390 is time-dependent. These results support a role for D-1 dopamine receptors in the nucleus accumbens and amygdala in the effects of self-administered cocaine, and suggest that D-1 receptors in certain portions of the 'extended amygdala' may be an important substrate for the reinforcing actions of cocaine.

Felbamate, a novel antiepileptic agent, does not affect cognition in rodents.

Felbamate is a novel anticonvulsant agent recently approved by the FDA for treatment of epilepsy in the US. While the mechanism of action of felbamate has not been fully eludicated, recent evidence has accumulated to suggest that felbamate may act at the strychnine-insensitive glycine binding site on the NMDA receptor complex. Since this receptor has been strongly implicated in cognitive processes, the current study was designed to investigate the potential effects of felbamate on learning performance. Doses of felbamate up to 1000mg/kg, administered subcutaneously (s.c.), did not produce deleterious effects on performance in either mice or rats, using a passive avoidance task. In contrast, the non-competitive NMDA antagonist dizocilpine produced performance deficits at doses from 0.1 to 1.0mg/kg s.c. in both rats and mice. Felbamate and dizocilpine prevented NMDA-induced convulsions with ED(50)s of 20.3 and 0.82mg/kg s.c., respectively. Calculations for the therapeutic index (ratio of the deficit-producing to anticonvulsant doses) for dizocilpine resulted in less than a 1-fold separation in dose, while the therapeutic index for felbamate was greater than 50. Taken together, these results indicate that felbamate does not produce cognitive deficits at doses more than 50 times the dose needed to block seizure activity in animals.

Methylatropine blocks the central effects of cholinergic antagonists.

These studies were conducted in order to establish the dose dependency and relative peripheral versus central activity of four prototypical cholinergic antagonists on the rodent passive avoidance response, a widely used animal model of retention. Subcutaneous administration of 0.1 to 100mg/kg revealed a potency profile of scopolamine > atropine methylscopolamine >/= methylatropine for the impairment of passive avoidance responding. A series of neurological assessments of the doses used indicated that side effects alone were not sufficient to impair passive avoidance responding. Although inactive when delivered peripherally, methylatropine was able to produce retention deficits at 10nmol (3.66µg) when administered intracerebrally. To further evaluate whether systemic methylatropine could enter the central nervous system, either scopolamine or atropine was administered subcutaneously in mice and rats pretreated with 10-100mg/kg methylatropine. The deficit-producing effects of scopolamine and atropine were abolished with methylatropine. Thus methylatropine is an exclusive peripheral antagonist; its ability to block the deficit-producing effects of scopolamine and atropine may occur through a change in blood-brain barrier permeability or through uncharacterized pharmacokinetic properties.

Determination of plasma and brain concentrations of SCH 39166 and their correlation to conditioned avoidance behavior in rats.

Plasma and brain concentrations of the dopamine D1 receptor antagonist, SCH 39166, were measured and compared to behavioral activity in the conditioned avoidance response paradigm (CAR). SCH 39166 was administered at two behaviorally active doses (1 mg/kg, SC and 10 mg/kg, PO) and the time course for CAR activity was compared with the plasma and brain concentrations of unconjugated SCH 39166. Conjugation and N-demethylation of SCH 39166 after oral administration were also determined and first pass metabolism examined. Results from these studies demonstrated a similar time-dependent disappearance of unconjugated SCH 39166 from both the plasma and brain, independent of route of administration. Brain concentrations of SCH 39166 were approximately 5-fold higher than corresponding plasma concentrations, regardless of route. However, plasma and brain concentrations of unconjugated SCH 39166 were higher after SC administration of 1.0 mg/kg, than after PO administration of 10 mg/kg, suggesting a substantial first pass metabolism of SCH 39166. In addition, total (conjugated and unconjugated) plasma concentrations of SCH 39166 were at least 10-fold higher than unconjugated concentrations of SCH 39166 after PO administration of 10 mg/kg, demonstrating that a high proportion of drug was conjugated. Metabolism to the N-desmethyl analog, SCH 40853, was observed after PO administration of 10 mg/kg SCH 39166 and a high proportion of conjugation of the desmethyl analog was also seen. Finally, plasma concentrations of unconjugated SCH 39166 exhibited a high positive correlation (r = 0.934, P < 0.001) with brain concentrations of unconjugated SCH 39166.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo binding to dopamine receptors: a correlate of potential antipsychotic activity.

Antagonists of dopamine receptors (especially those of the D2 subtype) have long been recognized as effective antipsychotics. SCH 39166, a dopamine D1 selective antagonist, is now also being evaluated for its clinical antipsychotic properties. The studies described herein determine the binding affinity of a variety of dopamine receptor antagonists (both dopamine D1 and D2 selective compounds) for the dopamine D1 and D2 receptors, in vivo, and correlate this affinity with their behavioral activity in the rat conditioned avoidance response (CAR) test. The in vivo binding affinities of the D1 selective compounds at the dopamine D1 site exhibited a high correlation (r = 0.97) with their activities in the rat CAR test. Likewise, D2 selective compounds' inhibition of in vivo binding to dopamine D2 receptors correlated with their behavioral potencies (r = 0.98). Conversely, any binding of selective agents to their non-targeted receptor did not correlate with their behavioral activity. These data suggest that in vivo binding to either dopamine D1 and/or D2 receptors is predictive of potential antipsychotic efficacy.

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.

[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.

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.

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)

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.

Psychomotor-stimulant effects of 3-isobutyl-1-methylxanthine: comparison with caffeine and 7-(2-chloroethyl) theophylline.

The behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) were compared with those of caffeine and 7-(2-chloroethyl) theophylline (7-CET) in squirrel monkeys under a multiple schedule of reinforcement in which fixed-interval responding was maintained alternately by presentation of food and presentation of electric shock. All three drugs produced dose-related increases in response rate in both components of the multiple schedule. Thus, although IBMX generally lacks psychomotor-stimulant effects in rodents, it had behavioral effects in squirrel monkeys that were qualitatively similar to those of caffeine. Based on the average ED50 values, IBMX was 5-7 times more potent than caffeine and 7-CET was twice as potent as caffeine in the two schedule components. This potency relation corresponds well with those observed in radioligand binding assays for central adenosine receptors and is consistent with the view that the psychomotor-stimulant effects of methylxanthines are linked to their antagonistic actions at the adenosine-receptor level. There was no obvious correspondence between the capacity of the methylxanthines to increase response rate and their capacity to inhibit phosphodiesterase activity.

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)

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.