Dihydrexidine: a new potent peripheral dopamine D1 receptor agonist.

Dihydrexidine (trans-10,11-dihydroxyhexahydrobenzo-[a]phenanthridine) was found to be a full dopamine D1 receptor agonist with a potency five times that of dopamine. Dihydrexidine showed no agonist activity at peripheral dopamine D2 receptors, alpha- or beta-adrenoceptors at the doses which produced near maximal stimulation of dopamine D1 receptors. The chemical structure of dihydrexidine shows that addition of a phenyl ring to a benzo[f]quinoline moiety bestows potent D1 activity upon a structure which had no such activity previously. This observation introduces a new factor in structure-activity considerations for dopamine receptor ligands.

Studies on the location of catecholamine receptors in canine sympathetic ganglia.

Receptors mediating catecholamine-induced inhibition were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Using selective agonists and antagonists the presence of three receptor subtypes was verified: alpha 1- and alpha 2-adrenoceptors and dopamine D2 receptors. Activation of alpha 1-adrenoceptors or dopamine D2 receptors reduced the response to preganglionic nerve stimulation but not to direct stimulation of the nicotinic acetylcholine receptors of the principal ganglion cells: response to both types of stimulation were reduced by activation of ganglionic alpha 2-adrenoceptors. These results suggested that two inhibitory systems were present in canine sympathetic ganglia and mediated the effects of exogenous catecholamines. One system involved alpha 1-adrenoceptors and dopamine D2 receptors located proximal to the synapse of the pre- and postganglionic neurons and the other involved alpha 2-adrenoceptors located distal to the intraganglionic synapse.

Studies on the functional role of alpha-adrenoceptors in the cardiac sympathetic ganglia of the dog.

Inhibitory alpha-adrenoceptors were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Blockade of alpha 1- or alpha 2-adrenoceptors augmented preganglionic nerve stimulation induced tachycardia without altering the response to postganglionic nerve stimulation. The effect produced by blockade of ganglionic alpha 1-adrenoceptors with terazosin had different frequency-response characteristics from, was of smaller magnitude than, and was additive with the effect produced by blockade of ganglionic alpha 2-adrenoceptors with rauwolscine. The response to activation of ganglionic nicotinic cholinergic receptors in the absence of electrical stimulation of the preganglionic nerve was not affected by blockade of either alpha 1- or alpha 2-adrenoceptors. The response to nicotinic cholinergic receptor activation during periods of continuous preganglionic nerve stimulation was augmented following blockade of alpha 2-adrenoceptors but unaffected by alpha 1-adrenoceptor blockade. These results suggest that there are two different inhibitory pathways involving alpha-adrenoceptors in mammalian sympathetic ganglia and provide evidence that these inhibitory pathways are operative under the experimental conditions of ganglionic transmission.

Absence of postsynaptic DA2 dopamine receptors in the dog renal vasculature.

In experiments designed to look for functional postsynaptic DA2 dopamine receptors in the dog renal vasculature, the vascular effects of two selective DA2 receptor agonists, bromocriptine and quinpirole, were studied in pentobarbital-anesthetized dogs. Intra-arterial (i.a.) injections of bromocriptine reduced renal blood flow before and after blockade of alpha-adrenoceptors. I.a. quinpirole produced dose-related increases in renal blood flow which were not altered by blockade of alpha- or beta-adrenoceptors or DA1 dopamine receptors. Neither of the selective DA2 dopamine receptor antagonists, domperidone or YM 09151-2, altered the renal vascular effects of quinpirole, but these were reduced by combined H1 and H2 histamine receptor blockade. The results of these experiments do not support the existence of postsynaptic DA2 dopamine receptors mediating vasodilation in the canine renal vasculature.

Catecholamine injections in canine paravertebral ganglia produce hypotension by neurogenic vasodilatation.

In the present study the alpha 1 selective agonist phenylephrine (PE), the alpha 2 selective agonist clonidine (CLO) and the non-selective endogenous catecholamine norepinephrine (NE) and dopamine (DA) were injected directly into the blood supply of the paravertebral sympathetic ganglia (PSG) of anesthetized open-chest dogs. Intra-arterial injection of all agonists produced dose-dependent decreases in mean arterial pressure (MAP) and femoral vascular resistance (FVR) but had no effect on heart rate. Their potency order was CLO greater than NE greater than PE greater than DA. Intravenous injections of the medium dose for NE and PE produced significant increases in MAP, while the medium dose of CLO injected iv produced a small decrease in MAP. The ganglionic blocking agent, hexamethonium (10 mg/kg iv) completely eliminated the hypotensive response to all agonists. Intra-arterial administration of the alpha 1 selective antagonist terazosin (0.5 mg) significantly reduced the decrease in MAP produced by the ganglionic actions of PE, but had no significant effect on the response to CLO. In contrast, the alpha 2 selective antagonist rauwolscine (100 micrograms) significantly reduced the decreases in MAP produced by ia CLO, but not that produced by ia PE. However, both antagonists inhibited the hypotensive effect of NE and DA. These findings suggest that both subtypes of alpha-adrenoceptors, alpha 1 and alpha 2, are present in the PSG and that both subtypes are inhibitory since their activation results in reduced transmission of impulses through the ganglia.

Effect of ring fluorination of epinephrine on its cardiovascular adrenoceptor activities.

Effects of fluorine (F) substitution on the 2- and 6-positions of the catechol ring of epinephrine (Epi) on its alpha- and beta-adrenoceptor agonist activities were studied in anesthetized dogs. Increments in heart rate and contractile force were used as measures of beta 1-adrenoceptor activity, while increases and decreases in blood pressure and decreases and increases in femoral blood flow were used as measures of alpha- and beta 2-adrenoceptor activities, respectively. F substitution on the 2- and 6-positions of the catechol ring yielded compounds with opposite receptor selectivities: 2-FEpi was a selective beta-adrenoceptor agonist with little agonist activity at alpha-adrenoceptors, while the 6-F analog was a selective a-adrenoceptor agonist with no significant beta-adrenoceptor effects. Of added significance, 2-FEpi was more potent than Epi as a beta 1-adrenoceptor agonist, while 6-F Epi was more potent than the parent compound as an alpha-adrenoceptor agonist. The possible mechanisms for the effects of ring fluorination on the adrenoceptor activities of Epi and other sympathomimetic amines are discussed.

Inhibitory effects of catecholamines in the paravertebral sympathetic ganglia of the anesthetized dog.

alpha-Adrenoceptor agonists decreased mean arterial pressure when injected into the arterial blood supply of the paraspinal sympathetic ganglia of pentobarbital-anesthetized open-chest dogs. The hypotensive response occurred concomitantly with selective decreases of vascular resistance in the vessels innervated by neurons arising from these ganglia, and both of these responses were blocked by the ganglionic blocking agent, hexamethonium. The hypotensive response to phenylephrine was selectively blocked by terazosin; alpha 1 selective agonist, and antagonist, respectively, while the hypotension produced by intra-arterial clonidine was blocked by rauwolscine; alpha 2 selective agonist and antagonist, respectively. Either terazosin or rauwolscine reduced the hypotension produced by noradrenaline or dopamine. These results demonstrated the presence of both alpha 1- and alpha 2-adrenoceptors in the paraspinal sympathetic ganglia. Activation of either alpha-adrenoceptor subtype inhibited ganglionic transmission.

Peripheral dopamine receptors.

Since 1979 when two subtypes of peripheral dopamine receptors (DA1 and DA2) were first proposed, much progress has been made to confirm such a view. Cumulative experience with the dog in vivo models suggests that the potency order: fenoldopam greater than dopamine greater than dipropyl dopamine greater than apomorphine characterizes the DA1 receptor while the reverse order: apomorphine greater than dipropyl dopamine greater than or equal to dopamine much greater than fenoldopam distinguishes the DA2 subtype. SCH 23390 for the DA1 and domperidone and (S)-sulpiride for the DA2, as selective antagonists, clearly identify the two subtypes. Increase in cyclic AMP after DA1 activation and decrease after DA2 occupancy have been reported. However, how both increase and decrease in cyclic AMP transduce vascular relaxation remains to be explained. DA1 and DA2 agonist activities of two new structures, CY 208,243 (Sandoz) and dihydrexidine, are reported in this chapter. Addition of benzene to ergoline and benzoquinoline moieties rendered these molecules inactive on the DA2 receptor while bestowing DA1 agonist activity on these otherwise inactive molecules and even obviated the need for two OH groups for DA1 activity. It would appear that the current views on structural requirements for DA1 and DA2 agonist activities will require revision and reexamination.

Effects of alpha adrenoceptor and dopamine receptor agonists and antagonists on ganglionic transmission.

Effects of alpha adrenoceptor and dopamine (DA) receptor agonists and antagonists on ganglionic transmission were studied in pentobarbital-anesthetized, open-chest dogs. Changes in tachycardia produced by preganglionic cardiac nerve stimulation were monitored as a measure of ganglionic transmission. Several agonists, injected i.a. into the blood supply of the stellate ganglion, inhibited ganglion transmission. This effect was localized to the ganglion as none of the agonists, in the highest doses studied, inhibited tachycardia produced by postganglionic cardiac nerve stimulation. The potency order of the agonists was UK 14,304 (alpha-2 adrenoceptor agonist) greater than norepinephrine (NE) greater than dipropyl DA (DA2 dopamine receptor agonist) greater than DA greater than or equal to phenylephrine (alpha-1 adrenoceptor agonist) greater than fenoldopam (DA1 dopamine receptor agonist). UK 14,304 was over 200 times more potent than fenoldopam, being active in nanomole doses, whereas NE was more potent than DA. Rauwolscine, an alpha-2 adrenoceptor antagonist, antagonized the inhibitory effects of NE and DA and was the only antagonist, given i.a. or i.v., that facilitated ganglionic transmission; frequency-response curves of tachycardia induced by preganglionic nerve stimulation were dose-dependently augmented. SCH 23390, in double the full DA1 antagonist dose, had no effect on frequency-response curves or on NE- or DA-induced ganglionic inhibition. Domperidone antagonized the effect of DA but had no effect on ganglionic inhibition produced by NE or on frequency-response curves of tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine receptors in the stellate ganglion of the dog.

Effects of fenoldopam, a selective DA1 dopamine receptor agonist, and dipropyl dopamine and propylphenethyl dopamine, preferential DA2 dopamine receptor agonists, on ganglion transmission were studied in pentobarbital-anesthetized, open-chest dogs. Tachycardia induced by electrical stimulation (supramaximal voltage, 0.5 ms duration, 1-2 Hz) of the preganglionic cardio-accelerator nerves was monitored as a measure of ganglionic transmission. Drugs were injected into the costocervical artery (i.a.) close to the arterial supply of the ganglion. Doses required to produce 30-40% inhibition of ganglionic transmission by the i.a. route were 2-8 micrograms for dipropyl dopamine, 4-16 micrograms for propylphenethyl dopamine, and 100 micrograms for fenoldopam. At these doses none of the agonists affected tachycardia induced by electrical stimulation of the postganglionic nerve. Domperidone (5 micrograms/kg i.v.), a selective DA2 dopamine receptor antagonist, markedly antagonized the effects of dipropyl dopamine and propylphenethyl dopamine, but had only minor (and statistically insignificant) effects on the inhibitory effect of fenoldopam. SCH 23390 (5 micrograms/kg i.v.), a selective and potent DA1 antagonist, failed to modify the effects of any of the agonists. In a separate series, infusion of fenoldopam, 20 micrograms/kg per min i.v. for 5-7 min, facilitated postganglionic nerve stimulation and blocked the inhibitory effect of UK 14,304, an alpha 2-adrenoceptor agonist, on the postganglionic nerve. These results confirm and support the presence of DA2 but do not support the presence of the prototypal DA1 dopamine receptor in the mammalian ganglia. Furthermore, the alpha 2-adrenoceptor blocking property of fenoldopam points to the complication of using i.v. administration for studying its ganglionic actions while monitoring the target tissue effects in response to preganglionic nerve stimulation.

Potentiation by dopexamine of the cardiac responses to circulating and neuronally released norepinephrine: a possible mechanism for the therapeutic effects of the drug.

Dopexamine is a new dopamine receptor agonist which also inhibits the uptake of norepinephrine (NE) into sympathetic nerves. Dopexamine was infused intravenously (i.v.) in anesthetized dogs at a rate used for treatment of congestive heart failure (4 micrograms/kg/min) before and during i.v. infusions of NE (0.26 +/- 0.06 and 0.57 +/- 0.12 micrograms/kg/min) and before and during cardioaccelerator nerve stimulation (0.25 and 0.50 Hz). Increments in cardiac contractile force produced by both infusion rates of NE were greater during dopexamine infusion; increases in heart rate (HR) and mean arterial pressure (MAP) produced by the higher infusion of NE also were increased by dopexamine. During cardioaccelerator nerve stimulation, 0.25 and 0.50 Hz, the increments in HR were significantly greater during dopexamine infusion; MAP also increased significantly during cardioaccelerator nerve stimulation (0.50 Hz) in the presence of dopexamine. Plasma NE concentration was significantly elevated during infusion of dopexamine. However, dopexamine did not enhance the elevated plasma NE concentration produced by NE infusions. This study demonstrates that infusion of dopexamine potentiates the cardiovascular effects resulting from neuronally released and exogenously infused NE.

Relative DA1-dopamine-receptor agonist and alpha-adrenoceptor antagonist activity of fenoldopam in the anesthetized dog.

Relative DA1-dopamine-receptor agonist and alpha-adrenoceptor antagonist activities of fenoldopam were determined in pentobarbital anesthetized dogs. The renal vasodilating effect of intravenous infusions of fenoldopam was used as an index of its DA1-agonist activity. Inhibition by fenoldopam of femoral vasoconstriction produced by intraarterial administration of phenylephrine (a relatively selective alpha 1 agonist) and UK 14,304 ( a relatively selective alpha 2 agonist) was used to determine its alpha-adrenoceptor antagonist activity. Intravenous infusions of 0.1 and 0.2 microgram/kg/min of fenoldopam caused dose-related reductions in renal vascular resistance and mean arterial pressure. Higher rates of infusions of fenoldopam (2 and 5 micrograms/kg/min) were given after pretreatment with 50 micrograms/kg/min SCH 23390 (a DA1-selective antagonist) to attenuate DA1-mediated hemodynamic effects. After SCH 23390, the infusion of 5 micrograms/kg/min of fenoldopam produced approximately the same hypotensive and renal vasodilating actions as the 0.2 microgram/kg/min infusion without SCH 23390. Alpha-adrenoceptor blocking activity was not observed with the 0.1, 0.2, and 2 micrograms/kg/min infusions of fenoldopam. The 5 micrograms/kg/min infusion, however, produced 14 and 25% inhibition of the vasoconstrictor effects of phenylephrine and UK 14,304, respectively. These data indicate that fenoldopam decreases renal vascular resistance in doses which are 25 to 50 times less than the dose needed to antagonize alpha adrenoceptors.

Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog.

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.

Specific dopamine D-1 and DA1 properties of 4-(mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and its tetrahydrothieno[2,3-c]pyridine analogue.

The title compounds were prepared and examined to elucidate further the structure-activity relationships of dopamine agonists related to nomifensine. Two of the compounds, 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydrothieno[2,3-c]pyridine, have been reported in the patent literature. In stimulation of rat retinal adenylate cyclase, a measure of dopamine D-1 agonist activity, the tetrahydroisoquinoline was about equipotent to dopamine. The thienyl isostere had nearly twice the potency. Both compounds were potent vasodilators in the canine renal artery, producing dilation through stimulation of DA1 type peripheral dopamine receptors. A monohydroxy analogue, 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline, had only slight activity in the cyclase assay and was inactive in the canine renal artery. These results, combined with those from an earlier study, demonstrate that N-alkylation decreases both dopamine D-1 and DA-1 agonist potency, with activity ordered as H greater than methyl greater than ethyl greater than propyl. The results also demonstrate the necessity for the catechol function in this series.

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arteries and veins.

This investigation was undertaken to characterize the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arterial and venous preparations. Contractile responses to cumulative additions of phenylephrine (selective alpha 1-adrenoceptor agonist), UK-14,304 (selective alpha 2-adrenoceptor agonist), noradrenaline (non-selective alpha-adrenoceptor agonist), and dopamine (non-selective alpha-adrenoceptor agonist) were measured in the presence and absence of rauwolscine, a selective alpha 2-antagonist, and terazosin, a selective alpha 1-antagonist. Phenylephrine was a more potent agonist in the mesenteric artery than in the mesenteric vein; UK-14,304 exhibited the opposite profile of activity. Terazosin was a more potent antagonist than rauwolscine against each of the agonists, except dopamine, in the mesenteric artery but rauwolscine was more potent than terazosin in the vein. Terazosin and rauwolscine were equipotent in inhibiting the contractile responses to dopamine in the artery while rauwolscine was more potent than terazosin in the vein. The pA2 values measured in both vessels failed, however, to demonstrate a high selectivity for either alpha-adrenoceptor antagonist. These results suggest that the alpha-adrenoceptors in the canine mesenteric artery and vein exhibit pharmacological characteristic typical of both alpha 1- and alpha 2-adrenoceptor subtypes.

Relative activities of SCH 23390 and its analogs in three tests for D1/DA1 dopamine receptor antagonism.

Inhibitory activities of a series of analogs of SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine) in which the 7-chloro group was substituted by bromo, fluoro, methyl and methoxy groups, respectively, were compared in three tests for D1 and DA1 dopamine (DA) receptor antagonism: inhibition of DA-induced renal vasodilation in the anesthetized dog (DA1 receptor model), inhibition of DA-stimulated adenylate cyclase in the striatum of adult female rats (D1 receptor model) and displacement of [3H]SCH 23390 in the striatal homogenates of male rats. In addition the D2 receptor affinity of each of the compounds chosen was assessed via displacement of [3H]spiperone binding from rat striatum. S-enantiomers of the Cl and CH3 analogs were 200- to 700-fold weaker than the respective R-enantiomers in all three tests. The activity of all the R-enantiomers was in the nanomolar range and varied no more than 8-fold in all three tests. The F analog in the ligand binding test was the only exception, which was 30-fold weaker than the C1 analog. All of the R-enantiomers studied showed much weaker affinity for the D2 receptor, as assessed by displacement of [3H]spiperone binding. Similar enantiomer selectivity and parallel affinities of the R-enantiomers in the prototype models for D1 and DA1 receptors strengthen the evidence in support of identity between the D1 and DA1 dopamine receptors. These results further indicate that displacement of SCH 23390 in the ligand binding test reflects affinity of a compound for D1 and DA1 dopamine receptors.