Biomedical subjects

R J Gorczynski

Publications and source records attributed to R J Gorczynski.

At least 19 recordsLinked to original sources

PubMed2000

Low-dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group.

OBJECTIVES: This study was designed to evaluate the effects of low-dose enoximone on exercise capacity. BACKGROUND: At higher doses the phosphodiesterase inhibitor, enoximone, has been shown to increase exercise capacity and decrease symptoms in heart failure patients but also to increase mortality. The effects of lower doses of enoximone on exercise capacity and adverse events have not been evaluated. METHODS: This is a prospective, double-blind, placebo-controlled, multicenter trial (nine U.S. centers) conducted in 105 patients with New York Heart Association class II to III, ischemic or nonischemic chronic heart failure (CHF). Patients were randomized to placebo or enoximone at 25 or 50 mg orally three times a day. Treadmill maximal exercise testing was done at baseline and after 4, 8 and 12 weeks of treatment, using a modified Naughton protocol. Patients were also evaluated for changes in quality of life and for increased arrhythmias by Holter monitoring. RESULTS: By the protocol-specified method of statistical analysis (the last observation carried-forward method), enoximone at 50 mg three times a day improved exercise capacity by 117 s at 12 weeks (p = 0.003). Enoximone at 25 mg three times a day also improved exercise capacity at 12 weeks by 115 s (p = 0.013). No increases in ventricular arrhythmias were noted. There were four deaths in the placebo group and 2 and 0 deaths in the enoximone 25 mg three times a day and enoximone 50 mg three times a day groups, respectively. Effects on degree of dyspnea and patient and physician assessments of clinical status favored the enoximone groups. CONCLUSIONS: Twelve weeks of treatment with low-dose enoximone improves exercise capacity in patients with CHF, without increasing adverse events.

Adolescent↗

PubMed1991

In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent.

Platelet aggregation requires binding of fibrinogen (fgn) to activated platelets and inhibition of this binding blocks platelet aggregation. Synthetic peptides modeled after the platelet binding sequence on fgn block the platelet glycoprotein IIb/IIIa receptor and effectively inhibit aggregation. SC-47643 (SC) is a mimetic of the RGD-containing peptide sequence that is recognized by the platelet IIb/IIIa receptor. SC inhibited fgn binding to activated platelets (IC50: 1.0 x 10(-5) M) and prevented platelet aggregation in response to a variety of platelet agonists in both washed human platelets and platelet rich plasma (IC50's ranging from 4 x 10(-6) to 1 x 10(-5) M, respectively). SC inhibited collagen induced thrombocytopenia in the rat (ED50 0.07 mg/kg and t1/2 36 min). In dogs ex vivo collagen induced platelet aggregation was inhibited 50% after a bolus injection of 1.7 mg/kg. After a steady state infusion (2 hr), the ED50 was 0.03 mg/kg/min, with no effects on blood pressure, heart rate or platelet count. These data demonstrate that SC, a peptide mimetic of the natural fgn binding sequence, is capable of blocking platelet-fgn interactions and platelet aggregation.

Amino Acid Sequence↗

PubMed1991

Antiplatelet and antithrombotic effects of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition by arginine-glycine-aspartic acid-serine (RGDS) and arginine-glycine-aspartic acid (RGD) (O-me)Y (SC-46749).

Arginine-glycine-aspartic acid (RGD) is the minimal sequence in fibrinogen that leads to recognition and binding to the glycoprotein IIb/IIIa platelet receptor during aggregation. Analogs of tetrapeptides containing the RGD sequence have been previously shown to block fibrinogen binding to activated platelets in vitro. SC-46749 is an analog of arginine-glycine-aspartic acid-phenylalanine in which the phenylalanine is replaced by O-methyltyrosine. In this study the biological activities of SC-46749 were examined and its actions compared with the tetrapeptide arginine-glycine-aspartic acid-serine (RGDS), one of the natural sequences on the fibrinogen alpha chain that binds to platelets. In vitro, SC-46749 was more potent than RGDS in inhibiting fibrinogen binding (IC50: SC-46749, 27 microM; RGDS, 47 microM), in preventing ADP-induced aggregation in human platelet-rich plasma (IC50: SC-46749, 32 microM; RGDS, 95 microM) and in inhibiting thrombin-induced aggregation in washed human platelets (IC50: SC-46749, 23 microM; RGDS, 64 microM). In rats, SC-46749 prevented collagen-induced thrombocytopenia with an ED50 of 0.87 mg/kg whereas RGDS did not inhibit the response by 50% at doses up to 10 mg/kg. SC-46749 inhibited thrombus formation in an electrically damaged rat carotid artery in a dose-dependent fashion whereas the effects of RGDS were biphasic. RGDS appeared to delay thrombus formation at lower doses but had no effect at higher doses. When infused in dogs for 15 min, SC-46749 prevented ex vivo collagen-induced aggregation at 4 mg/kg/min. These data demonstrate that SC-46749 is a potent inhibitor of platelet aggregation and platelet-dependent thrombus formation.

Animals↗

PubMed1989

Prevention of reoccluding platelet-rich thrombi in canine femoral arteries with a novel peptide antagonist of platelet glycoprotein IIb/IIIa receptors.

The composition of an evolving arterial thrombus may be a determinant of how effectively pharmacologic agents prevent reocclusion after initially successful thrombolysis. In this study, reoccluding platelet- or fibrin-rich thrombi as delineated by scanning electron microscopy were produced selectively in the femoral arteries of dogs with the use of electrically induced vascular injury or implantation of copper wire, respectively. Initial thrombolysis after intravenous infusion of tissue-type plasminogen activator (1 mg/kg over 30 minutes) was less frequent in the preparation producing platelet-rich thrombi than in that producing fibrin-rich thrombi (lysis in 19 of 24 versus 18 of 18, p = 0.06). In dogs with initial arterial recanalization, intravenous infusion of arginine-glycine-aspartate-O-methyltyrosine amide (RGDY), which competes with fibrinogen for binding to platelet glycoprotein IIb/IIIa receptors, prevented reocclusion caused by recurrence of platelet-rich thrombi in six of six dogs within 90 minutes; reocclusion occurred in five of seven saline-infused control dogs (p = 0.02). RGDY was only partially effective in preventing reocclusion caused by recurrence of fibrin-rich thrombi (reocclusion in three of six versus five of six controls, p = 0.54). Similar results were obtained with aspirin in both preparations. At least 98% of platelet aggregation induced ex vivo by collagen was inhibited by either RGDY or aspirin. In contrast with aspirin, however, platelet function returned to normal within 1 hour after discontinuation of RGDY. Thus, the relative proportions of platelets or fibrin incorporated into thrombi influence the efficacy of both tissue-type plasminogen activator for inducing thrombolysis and antiplatelet agents for preventing reocclusion. RGDY is a potent, short-acting inhibitor of platelet aggregation that effectively prevents reocclusion under conditions in which platelet deposition predominates.

Amino Acid Sequence↗

PubMed1988

Beta-adrenoreceptor antagonist potency and pharmacodynamics of ASL-8123, the primary acid metabolite of esmolol.

The beta-adrenoreceptor antagonist properties of ASL-8123, the primary metabolite of esmolol, were determined in vitro and in vivo. ASL-8123 demonstrated weak competitive beta-adrenoreceptor blocking activity in isolated guinea pig right atria with a pA2 of 3.73 +/- 0.07; no agonist-like activity was observed in this tissue at concentrations of ASL-8123 from 3 X 10(-5) to 1 X 10(-2) M. In anesthetized dogs, ASL-8123 was infused at increasing dosages from 0.2-25.6 mg/kg/min, each dose rate maintained for 20 min. The compound produced a slight decrease in heart rate of 15-22 beats/min at cumulative doses of 508-1,020 mg/kg and decreased diastolic blood pressure by 14-47 mm Hg at cumulative doses of 252-1,020 mg/kg. ASL-8123 dose-dependently inhibited the heart rate and diastolic blood pressure responses to isoproterenol (0.5 micrograms/kg i.v.). Blood levels of ASL-8123 were linearly correlated with inhibition of the heart rate response to isoproterenol (r = 0.95-0.99 for each dog, n = 6). The blood level of ASL-8123 that produced a 50% inhibition of isoproterenol-induced tachycardia averaged 293 +/- 65 micrograms/ml. Recovery from beta-adrenoreceptor blockade after terminating the infusion of ASL-8123 occurred slowly, decreasing from 81% at the end of the infusion to 55% 60 min later, and was paralleled by a slow decrease in blood levels of ASL-8123. Thus, ASL-8123 is a weak beta-adrenoreceptor antagonist which is approximately 1,600-1,900 times less potent than its parent, esmolol.

Adrenergic beta-Antagonists↗

PubMed1987

Cardiovascular effects of chronic high-dose atriopeptin III infusion in normotensive rats.

Seventy-eight Sprague-Dawley rats received continuous intravenous infusions of either atriopeptin III (APIII), 60 micrograms/kg/hr, or distilled water vehicle for a period of 7 days by means of osmotic minipumps. On Day 7 approximately one-half of the animals (20 vehicle-treated rats and 21 APIII-treated rats) were instrumented for evaluation of cardiac function and terminated for measurement of heart weight. The minipumps remained in place during the evaluation of cardiac function. Also on Day 7, the osmotic pumps were removed from the remaining animals and an additional 7 days were allowed to elapse before heart weight and cardiac function were evaluated. Mean arterial blood pressure (MAP) of rats receiving APIII for 7 days was significantly lower (-9%, p less than 0.05) than that of rats receiving vehicle for 7 days. In addition, reductions (p less than 0.05) of total ventricular weightdry (-7%), left ventricular weightdry (-8%), and right ventricular weightdry (-9%) were observed in the APIII-treated rats (all ventricular weights are normalized for body weight). Hematocrit (HCT) was significantly higher (13%, p less than 0.05) in the APIII-treated group. Chronic APIII infusion did not influence ventricular performance nor did it affect regional vascular resistances. Seven days after termination of the APIII infusion the differences in MAP and HCT between vehicle-treated and APIII-treated animals were no longer evident. Partial recovery of the effect on heart weights was apparent, with total ventricular weightdry and left ventricular weightdry remaining slightly reduced (-4 and -5%, respectively; p less than 0.05). No differences were found between the two recovery groups for any index of cardiac function. In separate experiments, it was demonstrated that APIII, 60 micrograms/kg/hr iv, caused a significant increase in urine volume (p less than 0.05 relative to vehicle) during the initial 24 hr of infusion. The results indicate that chronic infusion of a large diuretic dose of APIII exerts relatively little influence on overall cardiovascular function in normotensive rats.

Animals↗

PubMed1987

Controlled beta-receptor blockade with flestolol: a novel ultrashort-acting beta-blocker.

The pharmacological properties of an ultrashort-acting beta-receptor blocking agent, flestolol, were evaluated in rabbits. Infusion of graded doses (1-100 micrograms/kg/min, i.v.) into conscious rabbits produced dose-dependent bradycardia without any significant effect on mean arterial pressure. A desired level of heart rate could be obtained by either increasing or decreasing the dose infused. Such titration could be done by changing the dose of flestolol at 20-min intervals. Infusion of 31 micrograms/kg/min of flestolol into reserpinized, conscious rabbits had no effect on mean arterial pressure or heart rate but produced significant inhibition of isoproterenol-induced hypotension and tachycardia. This dose had no effect on the chronotropic and vascular effects of norepinephrine (NE), angiotensin II, adenosine, or acetylcholine. In these rabbits, flestolol was greater than 10-fold as active as esmolol, another ultrashort-acting beta-blocking agent, in inhibiting the responses to isoproterenol. In rabbits under pentobarbital anesthesia, infusion of flestolol (3.1, 10, and 31 micrograms/kg/min) produced dose-dependent beta-receptor blockade. On termination of a 70-min infusion, recovery of the responses to isoproterenol occurred within 30 min. In a separate series of experiments, the effects of infusion of flestolol (10 micrograms/kg/min) into the portal vein were compared with the effects of infusion of the same dose of flestolol into the femoral vein of anesthetized rabbits. Infusion into the femoral vein produced bradycardia and inhibited the hypotensive as well as cardioaccelerator effects of isoproterenol. Infusion into the portal vein was devoid of either effect, suggesting extensive inactivation by the liver.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1986

Participation of the autonomic nervous system in the cardiovascular effects of milrinone.

The cardiodynamic activity of intravenously administered milrinone was examined in alpha-chloralose anesthetized dogs. Two groups of dogs were used, one pretreated with hexamethonium to block autonomic reflexes, and a second group which received no pretreatment. In the untreated group milrinone produced dose-dependent increases in +dP/dt and heart rate while decreasing both systolic and diastolic blood pressure and left ventricular end diastolic pressure (LVEDP). After treatment with hexamethonium basal heart rate was significantly increased, whereas reflex changes in heart rate in response to i.v. norepinephrine or nitroglycerin were ablated. Systolic, but not diastolic blood pressure was also markedly reduced by hexamethonium. In the presence of hexamethonium responses to milrinone were qualitatively similar to milrinone responses in the absence of hexamethonium. However, the dose-response curves for milrinone were shifted dextrally for changes in +dP/dt and LVEDP, whereas the dose-response curve for blood pressure was shifted sinistrally. Thus, it appears that the autonomic nervous system enhances the effect of milrinone on +dP/dt and LVEDP, but attenuates its effect on blood pressure.

Animals↗

PubMed1986

Pharmacology and pharmacokinetics of esmolol.

Esmolol is an ultra-short-acting beta-adrenergic blocking agent that possesses minimal partial agonist activity or direct membrane depressant activity. The short duration of action of esmolol is attributable to rapid enzymatic hydrolysis by red blood cell esterases, forming ASL-8123 and methanol. Experiments in the constant-flow-perfused isolated canine hindlimb indicate that therapeutic (beta blocking) doses of esmolol lack direct vascular effects and alpha-adrenergic blocking activity and that therapeutic doses do not interfere with vascoconstrictor effects of peripheral sympathetic nerve stimulation. Esmolol produces cardiac electrophysiologic and hemodynamic effects consistent with those of beta blockade. Specifically, esmolol decreases heart rate, depresses atrioventricular nodal conduction, and decreases determinants of myocardial oxygen demand. The beneficial antiarrhythmic and infarct-size limiting effects of esmolol have been demonstrated in several experimental models. Whereas beta blockers in general are effective in settings of supraventricular arrhythmias, sinus tachycardia, and myocardial ischemia, esmolol provides the added dimension of "titratability." Thus, the short duration of action of esmolol allows for very rapid titration to a preferred steady-state level of beta blockade; rapid adjustment to different steady-state levels of beta blockade, as may be required by changing status of the patient, and rapid disappearance of beta blockade following discontinuation of esmolol infusion, should this be necessary in the event of deleterious cardiac hemodynamic effects. Thus, esmolol is ideally suited for use in the treatment of patients in whom beta blockade is desirable, but in whom level of beta blockade must be very carefully modulated.

Adrenergic beta-Antagonists↗

PubMed1986

Comparison of the parasympatholytic activity of ACC-9358 and disopyramide.

ACC-9358 (N-[(3,5-di(pyrrolidinylmethyl)-4-hydroxy)benzoyl]aniline) is a newly developed analogue of changrolin, an antiarrhythmic agent used in the Peoples Republic of China. Since changrolin and other antiarrhythmic agents exert parasympatholytic activity which may limit their clinical usefulness, it was of interest to examine the parasympatholytic effects of ACC-9358. For comparative purposes we also studied the parasympatholytic activity of disopyramide. In guinea-pig isolated ileal strips, disopyramide, 3-30 microM, and ACC-9358, 100-300 microM, competitively antagonized carbachol-induced contractions with pA2 values of 5.78 and 4.17, respectively. In guinea-pig isolated right atria, disopyramide 3-30 microM, competitively antagonized methacholine-induced slowing of spontaneous beating with a pA2 value of 5.99 whereas ACC-9358, 3-300 microM, produced no significant muscarinic blockade in this preparation. Disopyramide (1.9-15 mg kg-1, i.v.), but not ACC-9358 (7.5-1.5 mg kg-1, i.v.), significantly increased rat pupil diameter in vivo. Disopyramide and ACC-9358 blocked vagal-induced reductions in heart rate in dogs anaesthetized with pentobarbitone. ED50 values were approximately 0.65 and 11.25 mg kg-1, respectively. We conclude that ACC-9358 possesses significantly less parasympatholytic activity than disopyramide.

Animals↗

PubMed1986

Pharmacodynamics and onset of action of esmolol in anesthetized dogs.

The pharmacodynamics and onset of action of esmolol, a novel, cardioselective beta adrenergic receptor antagonist with an ultra short duration of action, were studied in anesthetized dogs. Steady-state levels of beta blockade were attained within 10 min after initiation of esmolol infusion or when changing infusion rates. Similarly, steady-state blood levels of esmolol were attained within 30 min (the earliest sampling point) after starting an infusion and new steady-state blood levels were re-established again within 30 min after changing the infusion rates. Rapid recovery from beta blockade after termination of the esmolol infusion was paralleled by a rapid decline in blood levels of esmolol. The duration of action and elimination half-life both averaged less than 15 min. Excellent linear correlations were obtained between dose and steady-state blood concentration and the logarithm of the steady-state blood concentration and percentage of beta blockade. In a separate study, the onset of beta blockade with esmolol was observed within 15 sec of initiating a 60-sec infusion of 500 micrograms/kg/min. Peak beta blockade occurred at 30 to 45 sec after switching to a maintenance dose of 12.5, 25 or 50 micrograms/kg/min. The duration of peak effect was dependent on the maintenance dose. Peak blood levels of esmolol occurred immediately after stopping the loading dose and decreased to steady-state blood levels at 20 and 10 min after maintenance doses of 25 and 50 micrograms/kg/min, respectively. The results of these studies indicate that the onset, time to steady state and termination of beta blockade with esmolol are rapid and that an excellent correlation exists between the blood level of the drug and degree of beta blockade both during and after an esmolol infusion.

Adrenergic beta-Antagonists↗

PubMed1985

Basic pharmacology of esmolol.

Preclinical studies show that esmolol is an ultrashortacting, cardioselective beta blocker that possesses minimal partial agonist action or membrane-depressant properties. The electrophysiologic and hemodynamic actions of esmolol are the result of beta blockade. No direct, beta receptor-independent cardiovascular actions have been identified with beta-blocking doses in laboratory experiments. Because esmolol slows atrioventricular conduction, increases atrioventricular refractoriness and decreases the determinants of myocardial oxygen demand, it should have use in the treatment of supraventricular tachycardias and acute myocardial ischemia. Esmolol, because of its ultrashort duration of action, should be safe for the induction of beta blockade in patients who are critically ill and is ideally suited for rapidly changing levels of beta blockade in this clinical situation.

Adrenergic beta-Antagonists↗

PubMed1985

Role of alpha-adrenergic receptors in the intrinsic inotropic selectivity of dobutamine in anesthetized dogs.

The inotropic selectivity of dobutamine was examined in pentobarbital-anesthetized, vagotomized dogs pretreated with a ganglion blocker. The purpose was to determine if, in the presence of hexamethonium and vagotomy, the inotropic selectivity of dobutamine could be attributed to an action of dobutamine on alpha-adrenoreceptors. Dose-response curves were determined for either isoproterenol or dobutamine 30 min after treatment with hexamethonium (20mg/kg). Analysis of heart rate versus right ventricular contractile force showed that dobutamine produced less tachycardia for a given increase in contractile force than isoproterenol; this was statistically significant when contractile force was increased by either 50 or 100%. In a separate series of experiments, dobutamine (8 micrograms . kg(1-) . min(-1)) was administered 20 min after propranolol (3 mg/kg). Under these conditions there was a slight increase in contractile force which represented 12% of the dobutamine response prior to propranolol administration. This increase in contractile force in the presence of propranolol was completely prevented by the addition of phentolamine (1 mg/kg). Consequently, in another series of experiments, dose-response curves for dobutamine were performed in the presence of hexamethonium before and 30 min after phentolamine alone (1 mg/kg) or vehicle. Phentolamine did not influence the effect of dobutamine on heart rate or contractile force, but prevented the increase in diastolic blood pressure caused by dobutamine. In addition, analysis of heart rate versus contractile force indicated that there were no statistically significant effects of phentolamine on the inotropic selectivity of dobutamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1985

Cardiovascular pharmacology of ASL-7022. III. Peripheral vascular adrenergic mechanisms.

The peripheral vascular actions of i.v. administered ASL-7022 were investigated in anesthetized, open-chest dogs and in isolated hindlimbs of normal, acute baroreceptor-denervated and spinal dogs. ASL-7022 decreased diastolic arterial blood pressure in open-chest dogs, an effect which was inhibited by ganglion blockade (hexamethonium bromide, 10 mg/kg i.v.). In hindlimbs from control animals, ASL-7022 produced vasodilation. Propranolol (1.0 mg/kg i.v.) reduced but did not eliminate vasodilation in these preparations but combined beta adrenergic and ganglion blockade converted responses to vasoconstriction. ASL-7022 induced greater vasodilation in hindlimbs from acute baroreceptor-denervated animals than in control animals. In acute baroreceptor-denervated preparations ganglion blockade eliminated vasodilation, propranolol partially blocked vasodilation and combined beta adrenergic and ganglion blockade converted responses to vasoconstriction. In spinal dogs i.v. infusion of low doses of ASL-7022 induced small increases in perfusion pressure; higher doses produced small decreases in perfusion pressure. The compound caused only vasoconstriction in propranolol-pretreated hindlimbs and caused only vasodilation in phentolamine-pretreated hindlimbs. ASL-7022 also dose dependently inhibited vasoconstrictor responses to electrical stimulation of the lumbar sympathetic chain and to exogenously administered norepinephrine. The data suggest that ASL-7022 blocks sympathetic vasoconstriction by either inhibiting the sympathetic nervous system or by inducing postsynaptic alpha adrenoceptor blockade. The compound also produces beta adrenoceptor-mediated vasodilation and, under appropriate pharmacological conditions, can be demonstrated to produce alpha adrenoceptor-mediated vasoconstriction.

Animals↗

PubMed1984

[(Arylcarbonyl)oxy]propanolamines. 1. Novel beta-blockers with ultrashort duration of action.

Novel [(arylcarbonyl)oxy]propanolamines were synthesized and investigated as potential ultrashort-acting beta-adrenergic receptor blockers. Many of these analogues exhibited good potency and short duration. The N-ureidoalkyl analogue 85 (ACC-9089) has a potency equal to propranolol and a duration of action of about 21 min in the dog. It has been selected as a candidate for further clinical study. Structure-activity relationships and structure-duration relationships for these new beta-blockers are also discussed.

Adrenergic beta-Antagonists↗

PubMed1983

Ultra-short-acting beta-adrenergic receptor blocking agents. 3. Ethylenediamine derivatives of (aryloxy)propanolamines having esters on the aryl function.

Various ethylenediamine derivatives have been incorporated into the nitrogen substituent of certain short-acting (aryloxy)propanolamine systems that contain esters on their aryl functions. Although several of these compounds showed durations of action comparable to their prototypes, most of the nitrogen substituents significantly prolonged the duration of beta-adrenergic blockade. Similarly, while one of the compounds showed appreciable cardioselectivity in vitro, generally, little enhancement of cardioselectivity was obtained. A brief discussion of structure-activity relationships observed for the ethylenediamine derivatives is presented.

Adrenergic beta-Antagonists↗

PubMed1982

Ultra-short acting beta-blockers: a proposal for the treatment of the critically ill patient.

Beta-blockade is of proven value in the therapy of acute myocardial infarction but, unfortunately, may produce cardiac failure by removal of needed sympathetic support. The long duration of action of available blockers (hours) makes reversal of failure a complicated problem and precludes rapid modification of therapy to match changing autonomic conditions. To improve the safety and efficacy of beta-blockade in this setting we have developed the concept of ultra-short beta-blockade and have identified a novel beta-blocker (ASL-8052) which possesses a duration of action less than 15 minutes. This compound is cardioselective and possesses efficacy in an animal model of acute myocardial infarction. It, therefore, appears to be suitable for rapid attainment of controlled levels of beta-blockade via intravenous infusion and rapid recovery from beta-blockade if required by the clinical situation. The compound should, therefore, be useful for safe therapy in critically ill cardiac patients.

Adrenergic beta-Antagonists↗

PubMed1982

N-Aralkyl substitution of 2-amino-5,6- and -6,7-dihydroxy-1,2,3,4-tetrahydronaphthalenes. 2. Derivatives of a hypotensive-positive inotropic agent.

Seven derivatives of 2-[[2-(3,4-dihydroxyphenyl)-1-methylethyl]amino]-6,7-dihydroxy-1,2,3,4- tetrahydronaphthalene, an inotropic agent which also causes a decrease in blood pressure, were synthesized and tested for inotropic potency, cardioselectivity, and inotropic selectivity. The derivatives were designed to explore whether catechol moieties and rigid rotamers of dopamine are necessary for the activity which was found in the parent compound. The derivatives had phenolic functions in place of catechols, and they had phenethylamine in place of the tetrahydronaphthalene moiety. In no case was the profile of activity of the parent compound duplicated in the derivatives.

Animals↗