Renal,cardiac, and systemic hemodynamic effects of the dopamine receptor agonist SK&F 85174 in anesthetized dogs

SK&F 85174 is a mixed DA-1/DA-2 receptor agonist which is shown to inhibit sympathetic neurotransmission and cause hypotension in anesthetized animals. In this study, we have determined the regional and systemic hemodynamic effects of an intravenous infusion of SK&F 85174 (5 μg/kg/min for 5 min) in pentobarbital-anesthetized dogs and attempted to identify the dopamine receptor subtype(s) involved in the cardiac as well as vascular effects of this compound. SK&F 85174 produced significant decreases in mean blood pressure (MBP), left ventricular pressure (LVP), left ventricular dp/dt, total peripheral resistance (TPR) and renal vascular resistance (RVR), and a significant increase in renal blood flow (RBF). There were no significant changes in heart rate, cardiac output, coronary blood flow, or coronary vascular resistance. Prior treatment with SCH 23390 (DA-1 receptor antagonist) significantly attenuated the effects of SK&F 85174 on MBP, LVP, TPR, RBF, and RVR. In a second group of dogs S-sulpiride (DA-2 receptor antagonist) significantly antagonized the effects of SK&F 85174 on MBP, LVP, and dp/dt, but did not influence its effects on RBF, TPR, and RVR. These results show that (a) a decrease in total peripheral resistance and not the cardiac output accounts for the hypotensive action of SK&F 85174, (b) the renal hemodynamic effects of SK&F 85174 are mediated primarily via the activation of DA-1 receptors, and (c) whereas DA-1 receptors are involved primarily with the hypotensive action of this compound, it appears that activation of DA-2 receptors also contributes to the hypotension.     

Effects of SK&F 85174, a DA-1/DA-2 receptor agonist, on pre- and postganglionic sympathetic neurotransmission to the heart

We have performed experiments to determine the effects of SK&F 85174, a mixed DA-1/DA-2 receptor agonist, on the tachycardia elicited during pre- and postganglionic stellate stimulation in anesthetized dogs in order to identify a possible action of this compound on the stellate ganglia. SK&F 85174 produced hypotension and caused significant impairment of positive chronotropic responses elicited during pre- and postganglionic stellate stimulation. Pharmacological analysis of SK&F 85174-induced inhibition of cardiac sympathetic function with selective DA-1 and DA-2 receptor antagonists revealed that prior treatment with either S-sulpiride or domperidone (DA-2 receptor antagonists) significantly attenuated the inhibitory effects of SK&F 85174 on responses to pre- and postganglionic stellate stimulation. R-sulpiride (DA-1 receptor antagonist) failed to antagonize SK&F 85174-induced inhibition of tachycardia elicited during preganglionic stellate stimulation. Pretreatment with SCH 23390 (DA-1 receptor antagonist) did not modify the inhibitory effect of SK&F 85174 on responses to postganglionic nerve stimulation. However, SCH 23390 was most effective in antagonizing the hypotensive effect of SK&F 85174. These results show that SK&F 85174 inhibits sympathetic neurotransmission to the heart by activating presynaptic and possibly ganglionic DA-2 receptors, whereas the hypotension produced by SK&F 85174 results predominantly from the activation of the vascular DA-1 receptors. SK&F 85174 does not seem to exert any effect on the ganglionic DA receptors which are reported to be activated by the selective DA-1 receptor agonist, fenoldopam.     

Comparative studies of cardiovascular effects of a new dopamine agonist (SK&F 38393A) and dopamine

SK&F 38393A (DAA) dose-dependently decreased the contractility of isolated frog hearts with an ED50 of 6.60 +/- 0.28 X 10(-5) M, while, dopamine (DA) elicited a dose-dependent increase in the contractility of the preparation with an ED50 of 5.13 +/- 0.36 X 10(-5) M. The results of in situ investigation, using cardiac output as the index of cardiac contractility, were in agreement with the in vitro results. Haloperidol (10(-6) M), a dopaminergic receptor blocker, did not block the cardiovascular effects of DAA and DA. However, propranolol (10(-8) M), a beta-adrenergic receptor blocker, prevented the positive inotropic effects of DA but had no effects on the negative inotropic effects of DAA. The results suggest that DAA might be acting on this preparation through a mechanism which is probably not associated with beta-adrenergic and/or dopaminergic receptors.     

The central effects of a novel dopamine agonist

A new peripheral dopamine agonist which causes dopaminergic renal vasolidation, was tested for central dopaminergic activity. SK & F 38393 stimulated the dopamine-sensitive adenylate cyclase in homogenates of rat caudate, as a partial agonist, and caused contralateral rotation in rats with unilateral 6-OHDA lesions of substantia nigra. Rotation was shown to be due to a direct effect on supersensitive dopamine receptors. Stimulation of cAMP formation and rotation were blocked by dopamine antagonists. In contrast to other dopamine agonists, SK & F 38393 did not cause stereotypy, emesis or inhibition of prolactin release, nor did SK & F 38393 affect dopamine turnover. The results suggest that SK & F 38393 may selectively stimulate supersensitive central dopamine receptors in vivo or may activate only a certain subclass of dopamine receptors including the receptor in the renal vasculature and the adenylate cyclase coupled postsynaptic receptor in the caudate.     

Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist.

These studies characterise the pharmacology of ropinirole, a selective D-2 agonist. High-affinity human caudate binding revealed a Ki for D2 receptors of 2.9 x 10(-8) M with no affinity for D1 at 10(-4) M in the rat. Ropinirole was weakly active at alpha 2-adrenoceptors and 5-HT2 receptors but inactive at 5-HT1, benzodiazepine and gamma-aminobutyric acid receptors or alpha 1 and beta-adrenoceptors. In rodents, ropinirole, like apomorphine, caused biphasic spontaneous locomotor activity and contralateral circling in 6-OHDA-lesioned mice with no tolerance to the latter after 14 days treatment. Amphetamine caused ipsilateral responses in the lesioned mice. Ropinirole did not cause marked stereotypies. In marmosets ropinirole (0.05-1.0 mg/kg SC or 0.1 mg/kg PO) reversed all motor and behavioural deficits induced by MPTP. This response started 10-20 minutes after dosing, and exceeded 2 hours. No tolerance was seen following chronic b.i.d. treatment. Similar results were obtained with 1-dopa plus benserazide; however, 1-dopa always caused emesis, whereas beneficial effects were shown with ropinirole in the absence of this side effect. These results support the continued clinical assessment of ropinirole for the treatment of Parkinson's disease.     

Hyperthermia induced by the dopamine D1 receptor agonist SK&F38393 in combination with the dopamine D2 receptor agonist talipexole in the rat.

The present experiments were performed to investigate the effects of dopamine D1 receptor agonists given alone or in combination with dopamine D2 receptor agonists on body temperature in rats. The selective dopamine D1 receptor agonist, 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SK&F38393), produced hyperthermia. However, the dopamine D2 receptor agonist, B-HT 920 (talipexole), and the newly synthesized dopamine D2 receptor agonist, (S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzothiazole (SND 919), did not change the temperature. Interestingly, the SK&F38393-induced hyperthermia was enhanced by talipexole and SND 919. The drastic hyperthermia induced by combined administration of dopamine D1 and D2 receptor agonists was blocked by either the dopamine D1 receptor antagonist, SCH23390, or the dopamine D2 receptor antagonist, spiperone. On the other hand, treatment with prazosin, yohimbine, propranolol, scopolamine, or methysergide failed to affect the marked hyperthermia. The present results suggest that a functional link between dopamine D1 and D2 receptors may be synergistic in the regulation of body temperature and that concurrent stimulation of both dopamine D1 and D2 receptors thereby produces marked hyperthermia in the rat.     

Dihydrexidine, a novel selective high potency full dopamine D-1 receptor agonist

The effect of chronic treatment (10 days) with thioridazine (25 mg/kg per day, i.p.) on the increase in diastolic blood pressure induced by methoxamine and xylazine was studied in the pithed rat. The dose-response curve for methoxamine, but not for xylazine, was shifted to the left by the neuroleptic. These results indicate that postjunctional alpha 1-adrenoceptors in the rat blood vessels become supersensitive after long-term treatment with thioridazine.     

The selective dopamine D1 receptor agonist SK&F 38393: its effects on palatability- and deprivation-induced feeding, and operant responding for food

A series of experiments investigated the involvement of the dopamine D1 receptor subtype in relation to feeding responses. The selective D1 agonists, SK&F 38393 (1.0-20 mg/kg) and SK&F 75760 (5 mg/kg), significantly reduced palatable food consumption in nondeprived rats. The anorectic effect of SK&F 38393 (10 mg/kg) was additive with that of the selective D2 receptor agonist, N-0437 (0.3 mg/kg). In nondeprived mice, SK&F 38393 had a stereoselective effect to reduce palatable food intake. At a peripherally-selective dose (3.0 mg/kg), the peripheral dopamine D1 receptor agonist, fenoldopam, had no effect on food intake. At 10 mg/kg, however, it exhibited anorectic properties, although this may have been due to some penetration of the blood-brain barrier. In rats adapted to a food-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) produced significant dose-dependent reductions in consumption of powdered chow and in lever-pressing for food pellets on a FR8 schedule of reinforcement. In rats adapted to a water-deprivation schedule, SK&F 38393 (3.0-30 mg/kg) was substantially less effective in reducing water intake. The results are discussed in terms of a possible selective effect of D1 agonist activity on feeding behaviour.     

The anorectic effect of SK&F 38393, a selective dopamine D1 receptor agonist: a microstructural analysis of feeding and related behaviour

An observational study was undertaken to provide a microstructural analysis of the effects of the selective dopamine D₁ receptor agonist, SK&F 38393, on feeding and associated behaviours in the rat. Adult, male non-deprived rats were adapted to eating a meal of sweetened mash in a 30-min period. SK&F 38393 (3.0 and 10 mg/kg, SC) significantly reduced food consumption). It also reduced the frequency of feeding bouts and the local rate of eating, while there was an increase, at 10 mg/kg, in the mean duration of individual feeding episodes. The D₁ receptor agonist also reduced the total duration of locomotor activity, but did not affect the total duration of rearing, grooming, sniffing, oral behaviours (other than feeding), or resting. The frequency of bouts of locomotion, rearing, grooming, and sniffing were reduced by SK&F 38393. Consideration of the time-courses for the several responses suggested that SK&F 38393 did not materially affect the form and sequence of behavioural responses in the test, although some changes occurred.     

Behavioral effects of RO 41-9067: A novel D2 dopamine receptor agonist

The behavioral effects of a novel putative D2 dopamine (DA) receptor agonist, RO 41-9067 (RO), were investigated in the mouse and compared with those of the classic D2 agonist LY 171555 (LY) at equimolar doses. Both RO and LY dose-dependently increased defensive behavior in naive mice interacting with nonaggressive conspecifics at doses higher than 0.2 and 0.16 mg/kg, respectively. Moreover, low and intermediate doses of RO and LY decreased locomotor activity in mice tested individually in an automated apparatus. Finally, coadministration of the D1 selective agonist SKF 38393 and high doses of RO or LY induced the hyperactive response classically induced by high doses of the mixed D1/D2 agonist apomorphine in the mouse while the inhibitory effects of the lowest doses of RO or LY were not affected by coadministration with SKF. These results indicate that RO induces behavioral effects characteristic of a D2 selective agonist when tested in intact mice and suggest that at high doses this compound activates postsynaptic D2 receptors which also cooperate with D1 receptors in the stimulation of DA-induced behaviors, while at low doses it selectively activates DA autoreceptors or inhibitory DA receptors of the D2 type. © 1992 Wiley-Liss, Inc.     

新型多巴胺D2类受体部分激动剂brexpiprazole

在多巴胺D2类受体中,D2受体部分激动剂对中脑边缘通路可产生功能性拮抗作用,能有效的改善精神分裂症因D2过度活动引起的阳性症状;对中脑皮层通路可产生功能性激动作用,可改善D2功能低下所引起的阴性症状、认知损害。brexpiprazole是一种新型多靶点作用机制的用于精神障碍疾病的治疗药物,除主要具备多巴胺D2受体部分激动作用之外,还具备D3受体部分激动作用、5-HT1A部分受体激动作用和5-HT2A部分受体拮抗作用,是针对单胺类神经递质多靶点开发的同时具有抗精神分裂和抗抑郁作用的新药,目前正在进行Ⅲ期临床试验。     

Attenuation of adenylate cyclase-induced increases in renal sodium excretion by the dopamine D-2 receptor agonist SK&F 89124

1 Although the existence of D-2 receptor binding sites in kidney has been identified, their functional significance in terms of influencing renal sodium excretion is not clear. In the present study we have examined the renal effects of a selective D-2 receptor agonist, SK&F 89124, in anaesthetized rats. 2 Intravenous infusion of SK&F 89124 (0.3, 1 and 3 μg kg^?1 min^?1 respectively) produced dose-dependent decreases in mean arterial blood pressure, heart rate and renal blood flow without causing any significant changes in urine output, urinary sodium excretion, renal vascular resistance or glomerular filtration rate. The changes in blood pressure, heart rate and renal blood flow caused by SK&F 89124 were abolished by a selective D-2 receptor antagonist, domperidone (50 μg kg^?1 i.v. bolus; 10 μg kg^?1 min^?1). 3 Treatment with 3-isobutyl-l-methylxanthine (IBMX, 1 mg kg^?1 bolus i.v.) or forskolin (200 μg kg^?1 bolus i.v.) produced increases in heart rate, urine output and urinary sodium excretion, but there was no change in mean blood pressure. The natriuretic and diuretic response, but not tachycardiac response to IBMX or forskolin, was attenuated by SK&F 89124 (0.3 μg kg^?1 min^?1). 4 These results suggest that the selective D-2 receptor agonist, SK&F 89124, produced a significant decrease in blood pressure and heart rate via prejunctional D-2 receptor-mediated inhibition of noradrenaline release from postganglionic sympathetic nerve terminals. Although activation of renal tubular D-2 receptors had no significant effect on renal excretory function under basal conditions, it is likely that these receptors may exert an opposing effect on cAMP-mediated increases in renal sodium and water excretion.     

Opposite effects of SK&F 38393, a dopamine D-1 agonist, and SCH 23390, a dopamine D-1 antagonist, in tests of salt preference/aversion in the rehydrating rat

Male rats were adapted to a 22-hr water-deprivation schedule, and to a 15-min choice test, in which water was available in one drinking tube, and water, 0.064%, 0.16%, 0.4%, 1.0%, or 2.5% NaCl solution, respectively, was available in a second. A typical saline preference-aversion function was obtained. The selective dopamine D-1 agonist, SK&F 38393 (3.0 mg/kg, IP), significantly depressed choice of hypertonic saline solutions (1.0% and 2.5% NaCl solutions), without affecting preference for hypotonic saline solutions. In contrast, the selective dopamine D-1 antagonist, SCH 23390 (0.1 mg/kg, SC), significantly increased the preference measure in the case of hypertonic solutions. These data indicate a role for D-1 receptors in dopaminergic mediation of the descending limb of the saline preference-aversion function.     

CY 208-243, a novel dopamine D-1 receptor agonist, fails to modify dopamine release in freely moving rats

CY 208-243, a novel D-1 agonist structurally unrelated to other D-1 agonists, at doses which elicited behavioural stimulation with locomotion, sniffing and grooming, failed to modify the release and metabolism of dopamine (DA) in the nucleus accumbens and in the dorsal caudate of freely moving rats, as estimated by transcerebral dialysis. CY 208-243 prevented the increase of DA release and metabolism elicited by the specific D-1 antagonist, SCH 23390, but not by the specific D-2 antagonist, sulpiride. The results support the conclusion that CY 208-243 is an effective and specific D-1 agonist in vivo.     

Discriminative stimulus effects of BAY 38-7271, a novel cannabinoid receptor agonist

BAY 38-7271 [(-)-(R)-3-(2-hydroxymethylindanyl-4-oxy)phenyl-4,4,4-trifluoro-1-sulfonate] is a novel, highly potent and selective cannabinoid CB(1)/CB(2) receptor agonist with neuroprotective properties. It was the aim of the present study to further confirm its cannabinoid CB(1) receptor agonist properties in a highly sensitive in vivo assay. Male Wistar rats (n=24) were trained to discriminate BAY 38-7271 (0.05 mg/kg, i.p., t-30 min) from vehicle in a fixed-ratio:10, food-reinforced two-lever standard procedure. The animals acquired the discrimination after a median number of 52 training sessions. BAY 38-7271 generalized dose-dependently when tested after different routes of administration (ED(50): 0.018 mg/kg, i.p.; 0.001 microg/kg, i.v.; 0.18 mg/kg, p.o.). A time-dependency study indicated that the cue (0.05 mg/kg, i.p.) was detectable between 15 min and 4 h, with a maximum of generalization obtained at 30 min after administration. Pretreatment with the selective cannabinoid CB(1) receptor antagonist SR 141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] completely antagonized the effects of BAY 38-7271 (ID(50): 1.1 mg/kg, i.p.). Dose-dependent and complete generalization was also obtained after i.p. administration of the reference cannabinoid CB(1) receptor agonists HU-210 [(-)-11-OH-Delta(8)-tetrahydrocannabinol-dimethylheptyl, ED(50): 0.003 mg/kg], CP 55,940 [(-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol, 0.007 mg/kg], WIN 55,212-2 [(R)-4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphtalenylcarbonyl)-6H-pyrrolo [3,2,1-ij] quinolin-6-one, 0.28 mg/kg] and (-)-Delta(9)-tetrahydrocannabinol (0.34 mg/kg). The present study confirms that BAY 38-7271 is a highly potent cannabinoid CB(1) receptor agonist in vivo.     

Behavioral effects in the rat of dihydrexidine, a high-potency, full-efficacy D1 dopamine receptor agonist.

Dihydrexidine (trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phena nthridine) was reported recently to be the first full efficacy, potent D1 receptor agonist, but one also having some potency for D2 receptors. This study reports the effects of dihydrexidine on behavior of the rat. In study 1, the dose-response relationships of dihydrexidine (0.3 to 30 mg/kg) to various behaviors were assessed using direct observations. The frequency of three behaviors (grooming, sniffing, and locomotion) was significantly increased by this drug. The dose-response curve for drug-induced grooming approximated an inverted U shape. Dihydrexidine increased locomotion at two of the higher doses (3 and 30 mg/kg), and increased sniffing at doses greater than or equal to 1.0 mg/kg. Other behavioral topographies, such as licking, gnawing, and rearing, were not systematically affected by drug administration. Also, there was no indication of convulsion in any dihydrexidine-treated rat. In study 2, rats were pretreated with either the selective D1 antagonist SCH23390 or the selective D2 antagonist remoxipride prior to receiving dihydrexidine. SCH23390 antagonized the effects of dihydrexidine on grooming, locomotion, and sniffing. Conversely, remoxipride blocked dihydrexidine-induced locomotion, but had no effect on dihydrexidine-induced grooming or sniffing. Numerous behaviors are believed to be mediated by the interactions of D1 and D2 receptors. These data indicate that dihydrexidine can be an important tool for characterizing both the behavioral actions of D1 receptors, and the nature of D1/D2 interactions in mammalian brain. In addition, its high potency and full efficacy at D1 receptors, coupled with its significant D2 properties, may provide specific utility in certain clinical situations.     

AP-811, a novel ANP-C receptor selective agonist

AP-811 is a derivative of the Phe8-Ile15 region of atrial natriuretic peptide (ANP) and is one of the smallest linear ligands for ANP receptors. The binding and agonist activities of AP-811 have been compared with those of other ANP analogs for the ANP-A and ANP-C receptors. AP–811 binds with a high binding affinity to and is a strong agonist for the ANP-C receptor, indicating that the binding and agonist sites for this receptor are the same or near each other in the ANP sequence. In contrast, AP-811 showed no agonistic effect for the ANP-A receptor, although it could bind to this receptor. Comparing the biological activities of AP-811 with those of other ANP analogs, we propose that the binding and agonist sites for the ANP-A receptor may consist of separate regions of ANP. In conclusion, AP-811 is the smallest C-receptor-selective agonist.     

A-68930, a novel, potent dopamine D1 receptor agonist: a microstructural analysis of its effects on feeding and other behaviour in the rat

A-68930 [1R, 3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCI] is a novel, potent and selective dopamine D1 receptor agonist. Previous reports have shown that the selective D1 partial agonist, SK & F 38393, reduced food consumption in rats and mice. The aim of this study was to undertake a microstructural analysis of the effects of A-68930 on food intake and feeding behaviour in non-deprived male rats trained to consume a highly palatable diet in a 20min period. A-68930 (0.1-1.0mg/kg, s.c.) produced a dose-dependent reduction in food intake which was due to a reduction in the frequency of bouts of feeding but not to a reduction in bout duration. A-68930 had little effect on the latency to initiate feeding or on the local rate of eating. Hence, it had a selective action on the parameters of eating, which is distinctly different from the effects of selective D2 agonists or of indirectly acting psychomotor stimulants like cocaine. A-68930 also increased grooming by lengthening the grooming bouts, and reduced locomotion and rearing responses. At the largest dose, immobility was increased. The anorectic effect of A-68930 may reflect, at least in part, the increased grooming it produces.