多巴胺受体激动剂对兔动脉cAMP产生系统的影响

实验观察了选择性多巴胺（ＤＡ）ＤＡ１受体激动剂ｆｅｎｏｌｄｏｐａｍ与ＤＡ２受体激动剂ｐｒｏｐｙ１－ｂｕｔｙｌ－ｄｏｐａｍｉｎｅ（ＰＢＤＡ）对兔肾动脉,肺、肠系膜动脉和股动脉环磷酸腺苷（ｃＡＭＰ）产生系统的影响。结果表明：⑴除股动脉外,ｆｅｎｏｌｄｏｐａｍ均可浓度依赖性地增加肺动脉、肾动脉和肠系膜动脉ｃＡＭＰ的生成量。选择性ＤＡ１受体阻断剂ＳＣＨ２３３９０可以显著阻断ｆｅｎｏｌｄｏｐａｍ的效应,而Ｄ     

Effect of fenoldopam on preconstricted isolated salt-perfused rat lungs

Using an in situ isolated salt-perfused rat lung preparation, we investigated the pulmonary vascular response to fenoldopam (a highly selective dopamine (DA1) agonist) infused at six different doses ranging from 0.1 to 10,000 micrograms/kg, during prostaglandin F2 alpha- (PGF2 alpha) induced pulmonary vasoconstriction. These experiments were repeated after selective DA1-blockade with SCH 23390. Twelve experiments were performed to evaluate the effect of fenoldopam on base-line hemodynamics. Sixty experiments were performed after PGF2 alpha vasoconstriction. Thirty lung preparations were pretreated with SCH 23390. PGF2 alpha was infused into the pulmonary inflow catheter at 2.5 micrograms.kg-1.min-1 to give a sustained rise in mean pulmonary arterial pressure (5.0 +/- 1.0 mmHg). Fenoldopam, at doses of 0.1, 1, 10, 100, 1,000, or 10,000 micrograms/kg, was injected into the pulmonary artery (n = 5 blocked and n = 5 unblocked at each dose). Fenoldopam had no effect on hemodynamics in the absence of PGF2 alpha. In the unblocked group, after PGF2 alpha vasoconstriction, fenoldopam infusion resulted in a dose-dependent decrease in the mean pulmonary arterial pressure with a dose-response curve characteristic for a drug-receptor interaction [Response = -1.0 (log Dose) -1.6]. In the DA1-blocked group after PGE2 alpha vasoconstriction, the dose-response curve was shifted to the right but parallel to the unblocked group, indicating competitive receptor blockade [Response -0.8 (log Dose) -0.05]. We conclude that vasodilatory DA1-receptors are responsible for the observed results.     

D-2 dopamine antagonist-like effects of SCH 23390 on A9 and A10 dopamine neurons

The effects of SCH 23390 on d-amphetamine-induced suppression of A9 and A10 DA neuronal firing were determined. SCH 23390 potently reversed d-amphetamine on both A9 and A10 DA neurons. Compared to haloperidol, SCH 23390 was 5 times more potent on A9 DA neurons and 20 times more potent on A10 DA neurons. However, the magnitude of the reversal effect was greater with haloperidol than SCH 23390. In addition, haloperidol produced a further increase in firing of both A9 and A10 DA neurons after SCH 23390 maximally increased firing. It was concluded that SCH 23390 has D-2 DA antagonist-like properties, possibly mediated via an interaction at D-1 DA receptors, which may be functionally linked with D-2 DA receptors. The marked potency of SCH 23390 in reversing d-amphetamine could be due to its combined antagonist effects at 5HT2 and D-1 DA receptor sites.     

Effects of acute and long-term treatment with neuroleptics on regional telencephalic neurotensin levels in the male rat

By means of radioimmunoassay measurements of regional neurotensin (NT) levels in the forebrain of the male rat it was shown that selective D2 DA receptor antagonists, such as haloperidol and sulpiride, and unselective D1 and D2 antagonists such as thioridazine, flupenthixol clozapine and fluperlapine, can acutely increase NT levels in the striatum and the nucleus accumbens without affecting NT levels in the amygdaloid or anteromedial frontal cortex. Conversely, acute treatment with the D1 DA receptor antagonist Schering 23390 (SCH 23390) produced a selective reduction of striatal NT levels. After long-term treatment clozapine, fluperlapine or SCH 23390, tolerance developed with regard to their ability to modulate striatal and accumbens levels. No tolerance occurred after chronic haloperidol, chlorpromazine and sulpiride. The results indicate that the acute administration of D1 and D2 DA receptor antagonists differentially modifies NT levels in the striatum and nuc. accumbens, and that antipsychotic drugs showing a relative lack of extrapyramidal side effects may be characterised by a failure to maintain increased NT levels in the basal ganglia upon long-term treatment.     

Renal dopamine receptors are involved in the development of cardiac hypertrophy

The present study examined the effect of fenoldopam, a known dopamine-1 receptor (DA1) agonist in order to understand its involvement in the cardiac hypertrophic process. Male Sprague-Dawley rats underwent abdominal aortic constriction (AB) with placement of a suprarenal ligature while sham operated animals served as controls. The AB groupsshowed an increase in their heart wt, left ventricular (LV) wt, heart wt/body wt and LV wt/body wt ratio. Furthermore, the length of these hearts, as measured from the auriculoventricular border to the apex, LV wall and interventricular (IV) septal thickness were increased from control levels. Treatment with SCH 23390, a DA1 antagonist, on the other hand, was able to partially regress the cardiac hypertrophic changes. All these parameters were also increased in control animals treated with fenoldopam (F). Such changes were more striking in the F+AB group which showed a significant acceleration of the cardiac hypertrophic process on super-imposing the two treatments. Plasma dopamine and renin activity were increased in all the groups as compared to control. These results indicate that dopamine receptors are implicated in the development of cardiac hypertrophy.     

Evidence for the presence of both D-1 and D-2 dopamine receptors in human esophagus.

Clinical and pharmacological evidence suggested that dopamine is involved in the control of esophageal motility. The present study was designed to determine whether or not dopamine receptors are present in human esophagus. With this aim we measured adenylate cyclase activity as a biochemical index of dopamine receptor function in esophageal specimens taken from five patients during surgery for upper esophageal carcinoma. The selective D-1 agonist fenoldopam stimulated cAMP formation in the lower esophageal sphincter, but not in the esophageal body; this effect was prevented by the selective D-1 antagonist SCH 23390 and by d-butaclamol. Bromocriptine, a selective D-2 stimulator, inhibited adenylate cyclase activity in the lower esophageal sphincter, an effect blocked by the D-2 antagonist (-)sulpiride. No effects of bromocriptine were found in the esophageal body. These data indicate that both D-1 and D-2 receptors are present in the lower esophageal sphincter, but not in esophageal body and emphasize the role of dopamine in the regulation of esophageal function.     

Interaction of the D1 Receptor Antagonist Sch 23390 with the Central 5-HT System: Radioligang Binding Studies,Measurements of Biochemical Parameters and Effects on L-5-HTP Syndrome

Abstract

The interaction of SCH 23390 with dopamine (DA) and serotonin (5-HT) systems has been examined in vivo and in vitro. Like selective 5-HT₂ blockers, SCH 23390 inhibited in vivo [³H]spiperone binding in the rat frontal cortex (ID₅₀: 1.5 mg/kg) without interacting at D₂ sites. SCH 23390 was equipotent to cinanserin and methysergide. In vitro, SCH 23390 inhibited [³H]ketanserin binding to 5-HT₂ sites (IC₅₀ = 30 nM). Biochemical parameters linked to DA and 5-HT were not changed excepted in striatum where SCH 23390 increased HVA and DOPAC. In the L-5-HTP syndrome model, SCH 23390 clearly showed antagonism of 5-HT₂ receptors. SCH 23390 had weak affinity for 5-HT_1B (IC₅₀ = 0.5 μM), 5-HT_1A (IC₅₀ = 2.6 μM) and α;₁-adenergic receptors (IC₅₀ = 4.4 μM).     

Differential contribution of dopamine D1 and D2 receptors in the mu-opioidergic immunomodulation

The study has shown that activation of mu-opioid receptors by a highly selective agonist DAGO (100 microg/kg) results in a significant increase of the immune response to antigen (SRBC, 5% 10(8)) in CBA mice. Haloperidol (2 mg/kg), a selective antagonist of the postsynaptic dopamine (DA) receptors, prevented immunostimulating effect of DAGO. In contrast, selective D1--antagonist SCH 23390 (1 mg/kg) did not affect on DAGO-induced enhancing of immune reactivity. At the same time, the blockade of both types of DA receptors (D1 and D2) caused similar immunosuppressing effects. These data suggest a possible differential role for D1 and D2 receptors in mu-opioidergic immunomodulation.     

Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics

Neuroleptics such as thioxanthenes (cis($\text{Z}$)-flupentixol and cis($\text{Z}$)-clopenthixol) and phenothiazines (fluphenazine and perphenazine), which block both dopamine (DA) D-1 and D-2 receptors and the butyrophenones (haloperidol and spiroperidol), which block D-2 receptors only, are equipotent both behaviorally and clinically. A new compound SCH 23390 which selectively blocks DA D-1 receptors, resembles many neuroleptics in its pharmacological profile: antistereotypic effects in mice, rats and dogs, cataleptogenic effect and inhibitory effect on amphetamine circling. In contrast SCH 23390 has no effect on apomorphine-induced vomiting in dogs and little effects on 6-OHDA-denervated supersensitive DA receptors, stimulated by the DA agonist 3-PPP. In a series of experiments where methylphenidate-induced stereotyped gnawing in mice was inhibited by neuroleptics, it was shown that concomitant treatment with scopolamine or diazepam attenuated the effect of butyrophenones (D-2 antagonists). The same treatment attenuated the effect of phenothiazines, to a lesser extent, and hardly attenuated the effect of thioxanthenes and SCH 23390 at all. It is concluded that DA D-1 receptors are as important as D-2 receptors for the expression of neuroleptic activity in most animal models believed to be predictive of antipsychotic and extrapyramidal side-effect potential. However, the D-1 antagonist is less sensitive than D-2 antagonists to antimuscarinic compounds and benzodiapines.     

Hyperactivity induced by stimulation of separate dopamine D-1 and D-2 receptors in rats with bilateral 6-OHDA lesions

The effects of DA agonists and antagonists with different dopamine (DA) D-1 and D-2 receptor selectivity have been studied in rats with bilateral 6-OHDA lesions. The D-1 agonist SK & F 38393, the D-2 agonist pergolide and the mixed agonist apomorphine all induced marked hyperactivity in lesioned rats in doses which were without stimulant effect in sham-operated animals. The hyperactivity induced by SK & F 38393 was blocked by the DA D-1 antagonist SCH 23390, but unaffected by the D-2 antagonists spiroperidol or clebopride. Pergolide-induced hyperactivity showed the reverse selectivity. The mixed D-1/D-2 antagonists, cis(Z)-flupentixol and cis(Z)-clopenthixol, however blocked the effect of both agonists. Apomorphine-induced hyperactivity was neither blocked by selective D-1 nor D-2 antagonists, but was dose-dependently inhibited by cis(Z)-flupentixol and cis(Z)-clopenthixol. Potent blockade was also obtained by combined treatment with SCH 23390 and spiroperidol, indicating the need of blocking both D-1 and D-2 receptors simultaneously. The results indicate that D-1 and D-2 receptor function can be independently manipulated in denervated rats and they confirm similar results obtained in rats with unilateral 6-OHDA lesions using circling behaviour.     

Dopamine Depletion Preferentially Impairs D1 over D2-Receptor Regulation of Striatal In Vivo Acetylcholine Release

The roles of D2 and D1 dopaminergic receptors on the regulation of striatal acetylcholine (ACh) release in vivo were examined for a period of 120 min after acute (2 h) or prolonged (16 h) depletion of brain dopamine (DA) by alpha-methyl-p-tyrosine. The reduction of DA transmission did not affect basal ACh output after 2 h but markedly lowered ACh release by 16 h (50%). Acute alpha-methyl-p-tyrosine pretreatment prevented the reduction of ACh release by the D1 antagonist SCH 23390 and its increase by the D2 antagonist, remoxipride, consistent with a drastic reduction of DA transmission at both DA receptors. However, 16 h after alpha-methyl-p-tyrosine, the effect of remoxipride on ACh release was restored, but SCH 23390 still had no effect, suggesting that the D2 inhibitory tone on ACh release had recovered, whereas the reduction of the D1 facilitatory influence persisted. The D1 facilitatory control of ACh neurotransmission thus appears to be more sensitive than the D2 inhibitory control to a reduction in DA transmission. The new model of DA-ACh interaction resulting from these data casts fresh light on the relationship between changes in DA transmission and extrapyramidal motor function.     

Differential effects of dopamine D1 and D2 receptor antagonists on conditioned orienting behavior in the rat

Brain dopamine (DA) systems are known to be important in regulation of behavior conditioned to appetitive stimuli. Nevertheless, despite a large body of evidence showing behavioral deficits in the operant conditioning paradigm produced by DA receptor blockade, there have been relatively few studies directly assessing behavioral changes in classical conditioning paradigm under this drug treatment. By employing an appetitive Pavlovian conditioning task, the present work investigated the effects of selective D1 and D2 receptor antagonists on the expression and acquisition of the conditioned orienting response (COR) and food-cup approach. SCH23390 (0, 0.05, and 0.10 mg/kg) and raclopride (0, 0.1, and 0.2 mg/kg) were administered via an intra-peritoneal route in a between-group design. Data from Experiment 1 showed that both SCH23390 and raclopride suppressed expression of the COR and food-cup approach, but only the impairment produced by raclopride reached a significant level. In Experiment 2, with SCH23390 being administered during the acquisition phase, the suppressed COR was completely restored in a subsequent (24 h later) drug-free session. In contrast, the suppressed COR in raclopride-pretreated groups was only partially restored. These findings support the view that the DA system plays a role in the neural substrates underlying this appetitive conditioning. In addition, D2 receptors are more likely involved in the modulation of learning process of the COR than D1 receptors.     

Behavioral recovery after irreversible inactivation of D-1 and D-2 dopamine receptors

Irreversible inactivation of both D-1 and D-2 dopamine (DA) receptors by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) resulted in complete loss of stereotypy response to R-(-)-N-propylnorapomorphine (NPA; 0.1-1.0 mg/kg, s.c.) 24 hr later. Stereotyped sniffing recovered much more rapidly than oral behaviors. The D-2 antagonist sulpiride (200 mg/kg) and the putatively nonselective antagonist cis-flupenthixol (2 mg/kg), administered prior to EEDQ, prevented the loss of NPA-induced sniffing but only partially protected against loss of oral behaviors 24 hr later. Complete protection of both behaviors was seen after pretreatment with a combination of sulpiride and the selective D-1 antagonist SCH 23390 (1 mg/kg); pretreatment with the selective D-1 antagonist SCH 23390 alone, however, did not modify the rate of recovery of either behavioral response. The results suggest that either different populations of DA receptors mediate expression of these behaviors or stimulation of a small fraction of the total DA receptor pool may be sufficient to elicit sniffing but not oral responses. Furthermore, maintaining a normal complement of D-2 rather than D-1 receptors appears to be a critical determinant for the elicitation of these behaviors.     

Chronic estradiol treatment increases ovariectomized rat striatal D-1 dopamine receptors

Striatal D-1 dopamine (DA) receptors were investigated following chronic 17 beta-estradiol (10 micrograms, b.i.d., s.c., for two weeks) to ovariectomized (OVX) female rats. This treatment initiated the day after ovariectomy has revealed that the maximal density in homogenates of striatal D-1 DA receptors (Bmax) labelled with [3H] SCH 23390 was increased (44% without and 28% with 120 mM NaCl in the assay buffer). Estradiol treatments initiated 2 or 4 weeks after ovariectomy did not induce D-1 DA receptor binding modifications. The affinity (Kd) of the ligand for the receptor remains unchanged by the steroid treatment while NaCl increased both the density and the affinity of [3H] SCH 23390 binding to striatal D-1 DA receptors. By autoradiography, the increase of striatal [3H] SCH 23390 binding to D-1 DA receptors after chronic estradiol treatment was found to be homogenously distributed in this brain region. Thus, chronic treatment with estradiol of ovariectomized rats leads to an increased density of striatal D-1 DA receptors but, this hormonal modulation of D-1 DA receptors is lost when treatment is started 2 weeks after ovariectomy or later.     

Lack or Inhibition of Dopaminergic Stimulation Induces a Development Increase of Striatal Tyrosine Hydroxylase-Positive Interneurons

We examined the role of endogenous dopamine (DA) in regulating the number of intrinsic tyrosine hydroxylase-positive (TH⁺) striatal neurons using mice at postnatal day (PND) 4 to 8, a period that corresponds to the developmental peak in the number of these neurons. We adopted the strategy of depleting endogenous DA by a 2-day treatment with α-methyl-p-tyrosine (αMpT, 150 mg/kg, i.p.). This treatment markedly increased the number of striatal TH⁺ neurons, assessed by stereological counting, and the increase was highly correlated to the extent of DA loss. Interestingly, TH⁺ neurons were found closer to the clusters of DA fibers after DA depletion, indicating that the concentration gradient of extracellular DA critically regulates the distribution of striatal TH⁺ neurons. A single i.p. injection of the D1 receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 (0.1 mg/kg), the D2/D3 receptor antagonist, raclopride (0.1 mg/kg), or the D4 receptor antagonist, L-745,870 (5 mg/kg) in mice at PND4 also increased the number of TH⁺ neurons after 4 days. Treatment with the D1-like receptor agonist {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393 (10 mg/kg) or with the D2-like receptor agonist, quinpirole (1 mg/kg) did not change the number of TH⁺ neurons. At least the effects of {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 were prevented by a combined treatment with {"type":"entrez-protein","attrs":{"text":"SKF38393","term_id":"1157151916","term_text":"SKF38393"}}SKF38393. Immunohistochemical analysis indicated that striatal TH⁺ neurons expressed D2 and D4 receptors, but not D1 receptors. Moreover, treatment with the α4β2 receptor antagonist dihydro-β-erythroidine (DHβE) (3.2 mg/kg) also increased the number of TH⁺ neurons. The evidence that DHβE mimicked the action of {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390 in increasing the number of TH⁺ neurons supports the hypothesis that activation of D1 receptors controls the number of striatal TH⁺ neurons by enhancing the release of acetylcholine. These data demonstrate for the first time that endogenous DA negatively regulates the number of striatal TH⁺ neurons by direct and indirect mechanisms mediated by multiple DA receptor subtypes.     

The alpha1-adrenergic receptor not the DA(1)-dopaminergic receptor mediates cyclosporine-SKF38393 renovascular interaction

In this study, we investigated the effect of acute exposure to cyclosporine A (CyA) on renal vasodilations evoked by the DA(1) dopaminergic agonist SKF38393 and whether dopamine DA(1) receptors are directly involved in the interaction. Changes evoked by CyA in SKF38393 vasodilations were evaluated in phenylephrine-preconstricted isolated perfused rat kidneys in the absence and presence of SCH23390, a DA(1) receptor antagonist. SKF38393 (3 x 10(-8) to 3 x 10(-6) mol) produced dose-dependent reductions in the renal perfusion pressure that were significantly attenuated in tissues pretreated with SCH23390 or CyA. Unlike SKF38393, the vasodilatory action of sodium nitroprusside, a nitrovasodilator, was not altered by CyA. The attenuating effect of CyA on SKF38393 vasodilations was preserved in preparations pretreated with SCH23390, suggesting that sites other than DA(1) receptors may be involved in CyA-SKF38393 interaction. The study was then extended to investigate the possible involvement of renal alpha1-adrenoceptors in the interaction. Blockade of alpha(1)-adrenoceptors by prazosin (30 nmol/L) significantly reduced the vasodilatory effect of SKF38393 and virtually abolished the CyA-induced attenuation of SKF38393 responses. Further, CyA failed to alter SKF38393 vasodilations when the renal tone was raised with prostaglandin F2alpha (PGF2alpha), a vasoconstrictor whose effect is independent of alpha(1)-adenoceptors. Together, these findings support earlier reports that both DA(1) and alpha(1)-receptors mediate the renal vasodilatory action of SKF38393 and suggest that CyA interacts selectively with the alpha(1)-receptor component to compromise SKF38393 responses.     

Influence of D-1 receptor system on the D-2 receptor-mediated hypothermic response in mice

The hypothermia induced by apomorphine, a mixed dopamine (DA) agonist in male Swiss-Webster mice, was not blocked by the selective D-1 antagonist SCH 23390 but was completely blocked by the selective D-2 antagonists haloperidol, sulpiride and YM-09151-2. The selective D-1 agonist SKF 38393 did not elicit hypothermic response but the selective D-2 agonist quinpirole caused a marked lowering of rectal temperature. D-2 antagonists blocked this response to quinpirole. SCH 23390 enhanced and SKF 38393 attenuated the hypothermia induced by quinpirole. Ineffective doses of haloperidol and SKF 38393, when given together, completely blocked the effect of quinpirole. It was concluded that hypothermia is a D-2 receptor mediated response but modulated by the D-1 receptor system. In another series of experiments the influence of neuroleptics and antidepressants on the hypothermic effect of apomorphine and quinpirole was investigated. The hypothermic effect of a low dose (1 mg/kg) of apomorphine was blocked by the D-2 receptor antagonists, but not by classical antidepressants. However, the response to a high dose (10 mg/kg) of apomorphine was blocked by both classical antidepressants and D-2 antagonists (except haloperidol). These drugs did not show similar effect on quinpirole-induced hypothermia. It is clear that the hypothermic response, especially that of quinpirole, is not a suitable model for testing either neuroleptics or antidepressants.     

The discriminative stimulus properties of the D-1 agonist SK&F 38393 and the D-2 agonist (-)-NPA are mediated by separate mechanisms

The dopamine D-1 agonist SK&F 38393 (10 mg/kg) the D-2 agonist (-)-NPA (0.04 mg/kg) and d-amphetamine (1.0 mg/kg) were established as discriminative stimuli versus saline in rats. The stimulus induced by SK&F 38393 was stereoselective, since the R-(+)-, but not the S-(-)-enantiomer was effective. It was mimicked by two partial D-1 agonists with central effects, SK&F 75670 and Lu 24-040, but not by the peripheral agonist fenoldopam. D-2 agonists and d-amphetamine were ineffective. The effect of SK&F 38393 was antagonized by SCH 23390, but not by its inactive enantiomer SCH 23388 or by the D-2 antagonist YM 09151-2. The (-)-NPA stimulus was dependent on postsynaptic D-2 receptors: It was mimicked by quinpirole and pergolide in stimulant dosages, whereas the partial D-2 agonist (-)-3-PPP inhibited the effect of (-)-NPA. The dopamine synthesis inhibitor alpha-methyl-p-tyrosine did not antagonize the effect of (-)-NPA. Likewise, the above-mentioned D-1 agonists produced saline responding. D-amphetamine produced partial substitution to (-)-NPA. The (-)-NPA stimulus was blocked by YM 09151-2, but not by SCH 23390. In d-amphetamine-trained rats, quinpirole, (-)-NPA and pergolide produced generalization, whereas SK&F 38393 was ineffective. Both SCH 23390 and YM 09151-2 antagonized the effect of d-amphetamine. It is concluded that the cues induced by SK&F 38393 and (-)-NPA are mediated by separate D-1 and D-2 sites, whereas both sites contribute to the effect of d-amphetamine.     

The binding of SCH 39166 and SCH 23390 to 5-HT1C receptors in porcine choroid plexus

SCH 39166 is a novel benzonaphthazepine, which has been characterized as a potent and selective D1 antagonist. Recently, its D1 selective benzazepine predecessor, SCH 23390, has been shown to bind to 5-HT1C binding sites in the choroid plexus. Therefore, the present studies were undertaken to determine if SCH 39166 has any measurable affinity for 5-HT1C binding sites. Our results indicate that SCH 39166 exhibited poor affinity for the 5-HT1C receptor, with a Ki of 1327 nM. In contrast, SCH 23390 inhibited [3H]-mesulergine binding to 5-HT1C receptors with a Ki of 30 nM. The non-selective 5-HT antagonist, methysergide, inhibited binding with a Ki of 2.4 nM. Finally, studies with the stereoisomers of SCH 39166 and SCH 23390 demonstrated that stereoselectivity at the 5-HT1C site is significantly less than for the D1 site.