Search

Cardiovascular effects of methoxamine and some aminotetralin derivatives (5,8-ADT, DR-31 and DR-17) were studied after systemic intravenous or intraarterial injection into different perfused vascular beds in anesthetized dogs. Intravenous administration of the compounds produced dose-related prolonged increases in blood pressure, which were antagonized by phentolamine. After intro-arterial injection into the perfused hindlimb, mesenteric artery or the saphenous vein, all compounds produced dose-dependent increases in perfusion pressure indicative of vasoconstriction. Phentolamine antagonized these effects. It was demonstrated that desipramine significantly reduced the vasoconstricting actions of intra-arterially injected tyramine in the hindlimb, but did not alter the responses induced by methoxamine and the aminotetralin derivatives. The data indicate that these compounds elicit peripheral vasoconstriction in the dog, through a direct action on the alpha adrenergic receptors.

The dopaminergic activity of ten apomorphine analogs was studied in rats lesioned unilaterally with 6-hydroxydopamine in the nigro-striatal system. Of these ten compounds, N,N-dimethyl-5,6-dihydroxy-2-amino-tetralin (M-7), N-methyl-5,6-dihydroxy-2-aminotetralin (M-8) and N,N-dimethyl-4,5-dihydroxy-2-aminoindan (DDAI) exhibited potent dopaminergic stimulant activity by causing the rat to turn to the unoperated side. The turning behavior of apomorphine, M-7, DDAI and d-amphetamine were antagonized by haloperidol. M-7 and DDAI also induced pecking in pigeons and their effects were also blocked by haloperidol. It is concluded that M-7, M-8 and DDAI are direct acting central dopaminergic agents.

The following synthetic, structural analogs of dopamine (DA) were examined for their ability to produce hyperglycemia in conscious unrestrained rats: APO (apomorphine), RDS-127 (2-di-n-propylamino-4,7-dimethoxyindane), di-n-propyldopamine, 2-di-n-propylamino-5,6-dihydroxytetralin, 2-dimethylamino-6,7-dihydroxytetralin, lergotrile, pergolide, bromocriptine and d-amphetamine. All the compounds demonstrated dose- and time-dependent hyperglycemic actions. The most potent DA analog to induce hyperglycemia was 2-di-n-propylamino-5,6-dihydroxytetralin (0.18 mumol/kg) and, at the doses used, 2-dimethylamino-6,7-dihydroxytetralin produced the greatest elevation in blood glucose (227% control). APO and RDS-127 were used in experiments designed to provide additional mechanistic information concerning their hyperglycemic action. The hyperglycemia produced by APO or RDS-127 was blocked by adrenalectomy, adrenodemedullation or prior administration of pimozide, a DA receptor antagonist. Phentolamine, an alpha adrenergic receptor antagonist had no effect on the hyperglycemia induced by APO or RDS-127. Oral glucose tolerance tests indicated that APO and RDS-127 caused abnormal glucose tolerance and inhibited the compensatory increase in serum immunoreactive insulin. These effects were prevented by pimozide or phentolamine pretreatment. The potencies of the compounds to produce increases in serum glucose concentrations (SG), inhibit the accumulation of DOPA using the in vivo gamma-butyrolactone procedure (DOPA) and inhibit food intake (FI) were subjected to correlation analysis. Positive correlations were found for FI vs. DOPA, r = 0.96; SG vs. decreases DOPA, r = 0.98 and SG vs. FI, r = 0.98.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous publications on the title compounds, 1 and 2 ('A-4' and 'A-5'), reported pharmacological data on what were probably mixtures of optical isomers of unknown composition. The compounds can exist as an enantiomeric pair as well as a diastereomeric meso isomer. In the present work, all possible stereoisomers (meso and dextrorotatory and levorotatory isomers) of the piperidine derivatives 'A-4' and 'A-5' have been isolated, identified, and characterized, and pharmacological data have been obtained on all products. In all of the bioassays conducted, optical isomers of each structure exhibited similar qualitative and quantitative effects. We conclude that the stereochemical nature of the chiral centers bearing secondary alcohol groups in these molecules does not play a critical role in interactions with in vivo receptors, and therefore that the alcohol groups in 'A-4' and 'A-5' are not prime sites of interaction(s) with receptor(s).

Possible metabolic activation of the dopamine receptor agonist DK-118 (5-hydroxy-6-methyl-N,N-di-n-propyl-2-aminotetralin) was investigated in cats. Metyrapone, an inhibitor of oxidative drug metabolism, was given to cats before DK-118 and the pharmacologic effects of the dopamine agonist were compared to those observed in nonpretreated animals. A sensitive high-performance liquid chromatography assay using electrochemical detection was developed to monitor urine and plasma concentrations of DK-118 in metyrapone-pretreated and control animals. The DK-118-mediated inhibition of cardioaccelerator nerve stimulation-induced tachycardia was reduced markedly in cats pretreated with metyrapone but the pretreatment had no effect on the hypotension or bradycardia produced by DK-118. In a separate group of cats, the tachycardia inhibitory effect of a nonbioactivated dopamine agonist, dipropyldopamine, was unaffected by metyrapone pretreatment, confirming that the inhibitor of drug metabolism does not interfere with this dopamine receptor-mediated effect. Pretreatment with metyrapone before a 0.14-mumol/kg i.v. dose of DK-118 increased the half-life, reduced total drug clearance and increased urinary excretion of unchanged DK-118. All of the changes are consistent with a metyrapone-related inhibition of DK-118 metabolism. The results of this study show that inhibition of DK-118 metabolism reduces certain of its pharmacologic actions, indicating that one or more of the metabolites of the drug may contribute to its effects.

This study demonstrates that presynaptic dopamine receptors and alpha-2 adrenoceptors are pharmacologically different. A series of 2-aminotetralins, benzhydro[f]quinolines, benzhydro[g]quinolines, apomorphine and clonidine were studied to determine if they could stimulate presynaptic alpha-2 adrenoceptor and dopamine receptors. Presynaptic dopamine receptor activity was observed in di- and monohydroxy derivatives of 2-aminotetralins, dihydroxy derivatives of benzohydro[f]quinolines and benzohydro[g]quinolines and apomorphine. The greatest presynaptic dopamine receptor activity was observed with agents which maintained the dopamine moiety in the trans coplanar conformation. In contrast to these observations 1) monohydroxy derivatives of 2-aminotetralines were devoid of presynaptic alpha-2 adrenoceptor activity and 2) both cis and trans isomers of dihydroxy derivatives of benzohydro[f]quinolines and benzohydro[g]quinolines exhibited significant presynaptic alpha-2 adrenoceptors activity. These data suggest that presynaptic alpha-2 adrenoceptors and dopamine receptors represent separate functional entities. A discussion on the structure activity relationship associated with presynaptic alpha-2 adrenoceptor and dopamine receptor is provided.

The dimethyl derivative of dopamine is the most active agent for inhibiting responses induced by sympathetic nerve stimulation. The compound is also a vasopressor. The diethyl and dipropyl derivatives slowed heart rate and lowered arterial pressure. The dibutyl derivative appeared to be inactive. On intravenous infusion into dogs, the dimethyl, diethyl and dipropyl derivatives are rapid in onset for altering blood pressure and slowing heart rate. During a 25 min infusion period there was no evidence of tachyphylaxis. Following infusion of the compounds, inhibition of response to neural stimulation and hypotensive properties were terminated within minutes. The compounds are potent, short acting inhibitors of adrenergic transmission and apparently are acting through dopamine receptors located at presynaptic sites. A ganglionic inhibitory component may also contribute to diminished adrenergic activity.

If the right postganglionic cardioaccelerator nerves of cats are stimulated (2 Hz), dopamine, in the presence of cocaine, inhibits transmission. This inhibitory response is prevented by low doses of haloperidol. Phentolamine produces some antagonism and phenoxy-benzamine produces no antagonism to the dopamine-induced inhibition. It is postulated that dopamine receptors on the adrenergic nerve terminals modulate norepinephrine release.

The effects of 5-hydroxy-6-methyl-2-aminotetralins were evaluated for central and presynaptic peripheral dopaminergic activity. Di-ethyl (DK-121) and di-propyl (DK-118) derivatives inhibited the tachycardia produced by postganglionic cardioaccelerator nerve stimulation in the cat. This effect was blocked by haloperidol (100 micrograms/kg). DK-118 inhibited stimulation-induced contraction of the cat nictitating membrane. The pressor response produced by lumbar sympathetic chain stimulation in the isolated hindlimb of the cat was inhibited by DK-118 following intravenous administration. Reflex sympathetic activation produced by 30 sec bilateral carotid occlusion was also inhibited by DK-118 in the dog. Centrally, DK-118 caused contralateral circling behavior in rats who had unilateral lesions of the caudate nucleus. DK-118 did not effect DOPA levels in either the caudate nucleus or olfactory tubercle. In contrast, DK-121 decreased DOPA levels in the caudate nucleus but did not produce circling behavior in rats. Both compounds have weak emetic activity in dogs. These results suggest that DK-121 and DK-118 possess stimulant properties on dopaminergic receptors in the central and peripheral nervous system. However, DK-121 does not appear to stimulate postsynaptic dopamine receptors in the central nervous system.

A number of DATS have been studied for agonist activity with dopamine (DA) and beta (beta) type adenylate cyclases and the most potent ones were found among the 6,7-DATs and the 5,6-DATs, respectively. None of the compounds tested possessed antagonist activity. The observed activities were not expected on the basis of structural analysis of model compounds such as apomorphine and 6,7-dihydroxy-1-benzyltetrahydroisoquinoline. A new view was constructed which suggests that the nitrogens of the DAT compounds were positioned better than those of the model compounds with regard to their binding sites.

Clonidine-induced inhibitions of twitch responses of coaxially stimulated guinea-pig ileum and transmurally stimulated rat vas deferens were antagonized by yohimbine in a competitive manner. In contrast to rat vas deferens, clonidine caused desensitization of presynaptic alpha 2-adrenoceptors on cholinergic neurons of guinea-pig ileum. Cross desensitization was observed between clonidine and oxymetazoline. No cross desensitization between clonidine and morphine was observed and indicates that presynaptic alpha 2-adrenoceptors are involved in clonidine-induced desensitization of the presynaptic site in the guinea-pig ileum.

Gastric erosions were induced in intact and ovariectomized rats by subjecting them to 24 h restraint. In association with erosion, histidine decarboxylase was determined in the glandular portion of the stomach. Under these experimental conditions, 8 weeks ovariectomy significantly reduced the severity of restraint induced gastric erosions. Administration of estradiol benzoate 10 micrograms/d for 4 weeks before restraint did not influence the severity of the erosions in either the control or ovariectomized rats. Lithium chloride 2mEq/kg given daily for 7 weeks to intact and ovariectomized animals did not modify the gastric erosion severity. However, combined treatment with estrogen and lithium, significantly decreased the severity of gastric erosions in intact but not in ovariectomized rats and this was associated with a significant increase in the endogenous histamine content of the gastric mucosa. The data show that ovariectomy protected rats against gastric erosions and that estrogen replacement treatment did not reduce the protection afforded by ovariectomy. They also demonstrate that estrogen-lithium administration reduces erosions and that the mechanism could be through decreasing histamine release from gastric tissue.

Dopamine receptor agonist activity was evaluated using resorcinol derivatives of the following ring systems: dopamine, aminotetralin, indan, benzocycloheptane, octahydrobenzo(f)quinoline and octahydrobenzo[g]quinoline. The compounds were evaluated for biological activity using in vitro binding assays, anesthetized cat blood pressure and heart rate, cat cardioaccelerator nerve preparation and rotations of rats with unilateral denervation of the caudate nucleus. Resorcinol substitutions were chosen because one hydroxyl group corresponded to the alpha-conformer of dopamine and the second hydroxyl group corresponded to the beta-conformer of dopamine. Dopamine receptor activity was found primarily with derivatives of aminotetralin and octahydrobenzo[f]quinoline while the other ring systems yielded compounds which were quite inactive. The active resorcinol derivatives were found in the same ring systems where catechol substitution was active in ring positions corresponding to either the alpha- or beta-conformer of dopamine. Likewise in those ring systems where catechol substitution corresponding to the beta-conformer of dopamine were quite inactive, resorcinol substitution in these series was not favorable for activity. The ring systems requirements for alpha- and beta-adrenoceptor agonist activity did not follow the same structural pattern as found for dopamine receptor agonist activity.

A series of heterocyclic congeners of dopamine (GJH-series) with different positions of phenolic oxygens and with the possibility of cis and trans isomerism at the 4a-10b ring juncture was evaluated in vitro and in vivo for dopaminergic activity. Two compounds, GJH-166 and GJH-171, were found to suppress the positive chronotropic response induced by stimulation of the right cardioaccelerator nerves. These effects were antagonized by haloperidol. GJH-166, in doses as low as 9.5 x 10(-4) mugmol/kg reduced the resting heart rate in cats anesthetized with alpha-chloralose. GJH-166 and GJH-171 antagonized pressor responses induced by bilateral carotid occlusion and stimulation of the central stump of the sciatic nerve. The results outlined in this manuscript support the hypothesis that the extended conformation of the dihydroxyhenylethylamine moiety of dopamine with a trans isomeric form is favorable for dopaminergic agonist activity.

M-7, in doses of 1 mug/kg, reduces the resting heart rate of anesthetized dogs and cats. In similar dose ranges, M-7 blocks reflex activation of the sympathetic nervous system. Experimental procedures included bilateral carotid occlusion in the dog and central stimulation of vagi and right sciatic nerves in the cat. M-7 inhibits the response to postganglionic stimulation of the right cardioaccelerator nerve if the frequency of stimulation is 2 Hz; no inhibition is observed with a frequency of 18Hz. The inhibitory action of M-7 is antagonized by haloperidol, 50 mug/kg, or chlorpromazine, 150 mug/kg. Similar inhibitory actions and frequency specificity were observed in vitro using the right atrium of the cat and nerve stimulation. In cats, nerve stimulation was inhibited by apomorphine. Dopamine, in the presence of cocaine, also inhibited low-frequency nerve stimulation. It is postulated that prejunctional sympathetic nerves innervating the heart have dopamine receptors that serve as inhibitory role in transmission.

An aminotetralin derivative, N,N-dipropyl-2-amino-1,2,3,4 tetrahydronaphtelene (TL-68) produced dose- and concentration-dependent inhibition of heart rate increases induced by stimulation of the cardioaccelerator nerves of anesthetized cats and by transmural stimulation of isolated cat right atria. These inhibitions were reversed by the dopaminergic antagonist haloperidol and not by the alpha2 adrenergic antagonist yohimbine. Results suggest that TL-68-induced inhibition of heart rate responses to stimulation of postganglionic sympathetic nerve endings is by stimulation of presynaptic inhibitory dopaminergic receptors in cat hearts. Since the compound is active in both in vivo and in vitro experiments, TL-68 apparently does not require metabolic activation before interaction with dopaminergic receptors.

In a continuing investigation of structural requirements for hemicholinium-like activity (inhibition of neuromuscular transmission due to inhibition of uptake of choline into nerve terminals), some additional molecular modifications of hemicholinium ("HC-3"; structure 1) were made. The target compounds were prepared by standard one- or two-step sequences. Noncyclic acetal moieties in general permitted retention of pharmacological activity, as did concomitant replacement of the central biphenyl "spacer" by other bulky cyclic groupings and replacement of the oxazinium rings by piperidine or 4-methylpiperidine. However, these modifications generally produced compounds of a lower potency. Replacement of the biphenyl moiety of HC-3 with polyakylene chains permitted retention of a considerable degree of activity. In these target compounds, the two quaternary nitrogens can exist the same distance apart (approximately 14 A) as in the hemicholinium molecule. The ditertiary amino congener of a pharmacologically active bis-quaternary oxazinium compound was almost completely inactive. To date, only one tertiary amine has been found which displays a significant degree of hemicholinium-like activity.

The ability of 2-aminotetralins (2-ATs), 2-aminoindanes (2-AIs), morphine (M) and clonidine (CLON) to alter neuroeffector transmission was studied on field-stimulated (FS) guinea-pig ilea (GPI). The activity of these compounds to inhibit K+, histamine (H), actylcholine (ACh), nicotine (Nic) and serotonin (5-HT) induced contractions was determined using superfused GPI segments. 2-ATs, 2-AIs, M and CLON dose-dependently inhibited contractions produced by low frequency stimulation through alpha-adrenergic, opioid or unknown receptor mediated mechanisms. 2-ATs inhibited ACh, Nic, 5-HT and FS, but not K+- or H-induced contractions. 2-ATs, 2-Ais and M were more potent than hexamethonium in inhibiting Nic-induced contractures. 2-AT and 2-AI-induced inhibition was not antagonized by naloxone or phentolamine. However, the inhibitory effects of 2-ATs. 2-AIs and M on FS-GPI were antagonized by increasing the concentration of Ca2+ ion in the media. These data are consistent with the supposition that 2-ATs, 2-AIs or M alter neuroeffector transmission through competitive changes in Ca2+ disposition in cholinergic neurons of guinea-pig isolated ilea. A discussion relating other biological actions of 2-ATs or 2-AIs (e.g. alpha-adrenergic mediated antinociception) to the observed inhibitory neuroeffector responses is provided.

The effects of prostaglandin A2 (PGA2) and prostaglandin B2 (PGB2) on vascular smooth muscle tone, electrolyte movements and responses to vasoactive stimuli were evaluated with superfused canine tibial arteries. PGA2 and PGB2 constricted superfused tibial arteries. PGB2 was 10.7 (8.3-14.1) times more potent as a constrictor than PGA2. PGA2 and PGB2-induced vasoconstriction was associated with a decrease in 22Na efflux and a tendency toward an increase in cellular sodium (expressed as micromoles per gram of wet weight). These prostaglandins also decreased the total potassium content of tibial arteries. 45Ca exchange was enhanced by PGA2 and PGB2. The time course of PG-induced increases in 45Ca efflux was similar to the temporal increase in force produced by PGA2 and PGB2. The duration of the contractile response to barium chloride was greatly prolonged during superfusion with both PGA2 and PGB2. These effects were probably not mediated by PG-induced alterations in the resting membrane potential of tibial arteries since presumed depolarization by both high potassium and zero-potassium physiologic saline solutions did not mimic the effects of these prostaglandins on vascular smooth muscle tone or responses to barium chloride. These data suggest that PGA2 and PGB2 may increase tone of vascular smooth muscle by inhibition of those processes involved in sequestration of calcium ion, i.e., the relaxation process, rather than acting on the contractile process.

The pharmacological effects of A-4, a bis 4-methylpiperidine tertiary amine derivative of hemicholinium-3, were investigated. Systemic administration (i.p.) of this compound produced a dose-dependent reduction in acetylcholine content of several brain regions. A dose of 40 mg/kg of A-4 produced a 40% reduction in acetylcholine content in the corpus striatum and this reduction was maintained for over 4 hr. Increased choline content was found concurrent with the reduction in acetylcholine content. Reversal of the A-4-induced reductions in acetylcholine content was seen with eserine and oxotremorine but not with choline chloride. Acute treatment with A-4 appeared selective for cholinergic neurons as no significant changes were seen in norepinephrine or serotonin parameters of any of the brain regions assayed. Dopamine turnover was increased in the striatum. The neurochemical changes produced by A-4 were not seen with the bis 4-methylpiperidine quaternary amine, A-5, or hemicholinium-3 after systemic administration of doses which produced pronounced behavioral and toxic effects. Intraventricular administration of A-5 or hemicholinium-3 produced a selective reduction in acetylcholine content. No changes were seen in dopamine, norepinephrine or serotonin parameters. Thus, A-4 represents a novel hemicholinium-3 analog in its ability to act centrally after systemic administration and may be potentially useful as a pharmacological tool in understanding cholinergic mechanisms in the central nervous system.

The dopaminergic and alpha adrenergic activities of TL-99 were investigated using in vitro preparations including cat right atria, guinea-pig atria, rat vas deferens and rabbit aortic strip. TL-99 was found to be as potent as clonidine as a stimulant of presynaptic alpha-2 adrenoceptors of noradrenaline nerve endings in guinea-pig atria and rat vas deferens. In the cat right atria, TL-99 preferently stimulates presynaptic dopamine receptors. The involvement of presynaptic alpha-2 adrenoceptor stimulation in TL-99-induced inhibition of tachycardic response to transmural stimulation in cat right atria is not clear. TL-99 is one thousand times less active as a stimulant of alpha-1 adrenoceptors of rabbit aorta than as a stimulant of presynaptic alpha-2 adrenoceptors of guinea-pig atria and rat deferens. Data from this manuscript as well as reports in the literature strongly suggest that TL-99 may interact with both alpha 2-adrenoceptors as well as dopamine receptors. The selectivity for receptor-type depends on test conditions, species variations and organ selectivity. The significance of these findings with TL-99 is discussed.

Previous reports suggest that analogs of dopamine (DA) can produce hyperglycemia in rats by interacting with DA receptors. Experiments reported here indicate the site of action and describe the metabolic sequalae associated with the hyperglycemic effect of apomorphine (APO), produced in conscious unrestrained rats. Apomorphine was more potent when administered by intracerebroventricular (i.c.v.) injection than when given subcutaneously (s.c.). Very small doses of the DA receptor antagonist pimozide, given intraventricularly, blocked the hyperglycemic effect of apomorphine administered subcutaneously. Sectioning of the spinal cord at thoracic vertebra T1-2 or sectioning the greater splanchnic nerve blocked apomorphine-induced hyperglycemia; whereas section of the superior colliculus or section at T5-6 had no effect. A dose of apomorphine or epinephrine (EPI) producing a similar degree of hyperglycemia elevated the concentration of EPI in serum to a similar degree, and the increase in EPI in serum preceded the increase in glucose in serum. Fasting animals for 2 or 18 hr had no significant effect on EPI- or apomorphine-induced hyperglycemia despite a reduction (91-93%) of the glycogen content of liver and skeletal muscle during the 18 hr fast. 5-Methoxyindole-2-carboxylic acid (MICA), an inhibitor of gluconeogenesis, blocked EPI- and apomorphine-induced hyperglycemia in rats fasted for 18 hr. However, 5-methoxyindole-2-carboxylic acid was ineffective in blocking hyperglycemia in animals fasted for 2 hr. Changes in insulin or glucagon in serum alone cannot account for the hyperglycemic action of apomorphine. These data demonstrate that apomorphine interacts with central DA receptors located in the hindbrain to activate sympathetic neuronal activity to the adrenal gland which subsequently releases epinephrine to alter homeostasis of glucose. Epinephrine may then, depending on the nutritional status, facilitate glycogenolytic or gluconeogenic processes to produce hyperglycemia.

A series of hydroxy 2-aminotetralins, benzhydro[f]quinolines and clonidine were used to determine whether a pharmacological similarity could be demonstrated between presynaptic alpha adrenoceptors which modulate autonomic transmission in the guinea pig. Compounds were assayed on isolated field stimulated guinea-pig ilea (GPI) to determine their inhibitory activities on cholinergic transmission. Inhibition of noradrenergic transmission was determined by assaying compounds on isolated field stimulated guinea-pig atria. 2-Aminotetralins, benzhydro[f]quinolines and clonidine impaired cholinergic and noradrenergic transmission by interacting with presynaptic alpha-2 adrenoceptors. A correlation (r = 0.95; P less than .05) was demonstrated between the activity of a compound on the GPI and guinea-pig atria. IC50 values obtained on GPI were correlated with previously reported IC50 values obtained for binding [3H]clonidine sites in homogenates of calf frontal cortex. A significant correlation was demonstrated (r = 0.99; P less than .05). These data suggest that alpha-2 adrenoceptors localized on guinea-pig atria and GPI are pharmacologically similar. In addition, a similar structure activity relationship was demonstrated for presynaptic alpha-2 adrenoceptors on GPI and binding sites labeled by [3H]clonidine in the calf frontal cortex.

Apomorphine (APO), 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127) and 2-di-n-propylamino-5,8-dimethoxytetralin (JMC-181) were examined on a variety of biochemical and pharmacological assays to determine their possible interaction with dopamine (DA) receptors. Nanomolar concentrations of all three compounds displaced [3H]APO from specific high-affinity binding sites in rat striatal membrane preparations, while higher concentrations were required to displace [3H]spiperone or [3H]rauwolscine. APO caused a concentration-dependent increase in the ability to stimulate postsynaptic DA receptors associated with adenylate cyclase (D1-sites) in the carp retina, whereas RDS-127 or JMC-181 were inactive in concentrations up to 300 microM. APO was very active in causing contralateral turning behavior in rats with a 6-hydroxydopamine lesioned substantia nigra (SN); RDS-127 was approximately 8 times less potent in producing contralateral rotations and JMC-181 was inactive. RDS-127 produced biphasic, dose-related changes in rat spontaneous locomotor activity similar to that reported for APO. The locomotor stimulant effects of RDS-127 were 3 times more potent and 4 times greater in duration than that induced by APO. JMC-181 produced primarily sedation in the doses tested. APO, RDS-127 and JMC-181 were active in inhibiting the accumulation of dopa in the caudate nucleus and olfactory tubercle using the in vivo gamma-butyrolactone procedure; 5-hydroxytryptophan accumulations were not altered significantly. RDS-127 was 7 times more potent than APO in inhibiting dopa accumulation in the caudate nucleus and equipotent to APO in the olfactory tubercle. Dopa accumulation was weakly inhibited by JMC-181. When single unit extracellular action potentials were recorded from purported DA-containing neurons in the SN, RDS-127 decreased the firing of neurons in the pars compacta of SN (ID100 = 40 +/- 10 nmol/kg i.v.). In contrast, firing of units in the pars reticulata of SN were not altered or increased in response to RDS-127. The biochemical electrophysiological and behavioral effects of RDS-127 were blocked or reversed by DA receptor antagonists. These data indicate that RDS-127 is significantly more selective than APO in preferentially activating DA autoreceptors as opposed to the postsynaptic DA receptors in the nigrostriatal pathway. The possibilities of designing potent, long acting, nonergot, noncatechol-containing DA receptor agonists are discussed.

In the anesthetized, open-chest dog, intravenous infusion 8– 13 microgram . kg-1. min-1) of a new dopamine analog 5,6-dihydroxy-2-methylaminotetralin hydrobromide (M-8) demonstrated potent coronary vasodilator properties. Blood flow to normal myocardium was increased an average of 53% above control flow values and this was associated with a decrease in coronary vascular resistance of 50%. The increase in blood flow was distributed uniformly to all portions of the myocardium (left ventricular free wall, right ventricular free wall, and septum). Subendocardial/subepicardial (endo/epi) flow ratios of the left ventricle, right ventricle, and septum were not significantly changed from control. In dog hearts subjected to acute, sudden occlusion of portions of the left anterior branch of the left coronary artery, M-8 produced a 93% increase in flow to the whole heart over postocclusion flow values. Flow to tissues of the heart made ischemic by the occlusive procedure in creased by an average of 94% during M-8 administration despite the fact that the occlusive ligatures remained in place. The vasodilation produced by M-8 was accompanied by a 22–24% increase in myocardial capillary surface area available for exchange of lipid-insoluble substances, fructose and sucrose. Hemodynamic changes associated with M-8 include a transient decrease in aortic pressure, but no change in heart rate, left ventricular (dP/dt)/P, or central venous pressure. Propranolol blocked the vasodilator activity of M-8. It was concluded that M-8 is a beta2-adrenergic receptor agonist having potent coronary vasodilator properties which also has the ability to open preexisting collateral blood flow channels and provide nutritive flow to ischemic, marginally ischemic, and normal myocardium. The cardiovascular actions of M-8 increase blood flow and oxygen delivery to the myocardium while decreasing the work and oxygen utilization by the heart, suggesting that it may have important antianginal characteristics.

Some derivatives of aminotetralins and their open chain analogs were tested for their ability to alter blood pressure and heart rate in anesthetized cats with both vagi nerves sectioned and their ability to relax tracheal smooth muscle of guinea-pigs. TL-257 and JOD-213, tertiary amines, produced weak alpha-adrenoceptor stimulating activity while JOD-176 and JOD-211, secondary amines, showed beta-adrenoceptor stimulating activity. Another compounds, M-8, an aminotetralin that is a secondary amine, produced alpha and beta adrenoceptor stimulating activity. The beta-adrenoceptor stimulating activities of M-8 and JOD-176 showed more specificity for beta2-adrenoceptors than for beta1-adrenoceptors.

The purpose of this research is the synthesis and biological evaluation of analogs of hemicholinium (HC-3). These are agents which decrease the ability of cholinergic neurones to synthesize acetylcholine. The long-range goal of this research is to develop compounds which can be used to antidote excess acetylcholine within a cholinergic synapse. Some possible approaches are 1) decrease the content of acetylcholine within the cholinergic neurone by interfering with synthesis, 2) desensitizing cholinergic receptors at post- synaptic sites, 3) decreasing the release of acetylcholine from the neurone by stabilizing the membrane or via pre-synaptic receptors which when activated will diminish the amount of acetylcholine released into the synapse. Thus far 3 agents have been prepared and evaluated for activity. Two of the agents, which are quarternary amines, approximate HC-3 in activity and the tertiary amine derivative is approximately 1/500th as active as HC-3. The latter agent is the first active non-quarternary amine to be reported. The biological assay procedures have been developed to evaluate these agents. Keywords: High performance liquid chromatography; Incubation; Caudate nucleus; Rats; Rabbits; Nerve-gastrochemisumuscle; In viro analysis; Neuro-muscular blocking; Phrenic nerve-diaphragm muscle; In vitro analysis; and Neuromuscular transmission.

Experiments were designed to determine the dopaminergic and alpha adrenergic receptors involvement of cis (CS-263) and trans (CS-265) isomers of nonhydroxylated N-propyl octahydrobenzo[f]quinoline. Both compounds caused competitive blockade of presynaptic alpha-2 adrenoceptors of guinea-pig ileum and rat vas deferens. Postsynaptic alpha-1 adrenoceptors of rabbit aorta was inhibited. In the guinea-pig ileum, these compounds were found to be as active as yohimbine. In the rabbit aorta, they were weaker antagonists of phenylephrine than prazosin. CS-compounds reversed epinephrine-induced pressor responses and inhibited reflex hypertensive responses to stimulation of the central stump of sciatic nerve in anesthetized cats. Only CS-265 inhibited reflex tachycardia of sciatic nerve stimulation. In isolated cat right atria, CS-265 inhibited stimulation-induced tachycardic response through stimulation of presynaptic dopamine receptors in contrast to CS-263 that produced potentiation of stimulation-induced tachycardia. The results suggest that CS-265 is an unusual compound having dopamine receptor stimulating activity and alpha adrenoceptor blocking properties. These divergent properties provide direct evidence that presynaptic alpha-2 adrenoceptors and dopamine-receptors are different entities on the sympathetic nerve terminal.

The effects of semirigid methoxy analogs of 2-aminotetralin (2-AT) and 2-aminoindane (2-AI) were studied on superfused dog metatarsal veins to investigate postjunctional interactions produced by these agents on sympathetically innervated vascular smooth muscle. The following compounds were tested: norepinephrine (NE); serotonin (5-HT); amphetamine (AMP); methoxamine (MTH); 2-di-n-propylamino-4,7-dimethoxyindane (RDS-127); 2-di-n-propylamino-5,6,-dimethoxyindane (JPC-211); 2-di-n-propylaminoindane (JPC-6036); 2-methylamino-5,8-dimethoxytetralin (DR-31); 2-methylamino-4,7-dimethoxyindane (RDS-31). The results of this study indicate that contractions produced by these compounds have the following ranked ordered potencies: 5-HT greater than NE much greater than MTH greater than or equal to RDS-127 = DR-31; JPC-6036, RDS-31, JPC-211 and AMP were inactive. The contractions produced by NE, MTH, RDS-127 or DR-31, but not 5-HT, probably occur through alpha1-adrenergic receptors since these contractions were blocked with prazosin. 5-HT and RDS-127, but not NE, MTH or DR-31 activate serotonin receptors since methysergide blocked the response produced by 5-HT or RDS-127. NE-induced contractions were augmented and tyramine-induced contractions were attenuated with cocaine. The responses of MTH, RDS-127 or DR-31 probably do not displace NE through a tyramine-like action since cocaine had no effect on contractions induced by these compounds. These data suggest that semirigid paramethoxylated derivatives of 2-AT and 2-AI are potent postjunctional receptor agonists which probably initiate venoconstriction via direct receptor interactions. The structure-activity relationships of these compounds are discussed.

Alterations in propylthiouracii (PTU) disposition after long-term use in patients treated for alcoholic liver disease (ALD) have not been reported. We gave PTU (3.3 mg / kg / day intraperitoneally) for 24 days to naive male Sprague-Dawley rats (n = 10). Clearance of PTU in these animals (1.11 ± 0.04 ml / min / kg, x ± SEM) was slightly less than in controls (1.28 ± 0.05 ml/min/kg, n = 8, P = 0.02) as a consequence of drug-induced hypothyroidism (thyroid weight in PTU-treated rats = 78.0 ± 7.2; controls = 29.6 ± 2.1 mg/kg, P < 0.01). PTU clearance in thyroidectomized rats (0.74 ± 0.04 ml/min/kg, n = 12; thyroid-stimulating hormone [TSH] = 3.3 ± 0.2; μIU/ml) was less (P < 0.01) than in sham-operated controls (1.47 ± 0.12 ml/min/kg; n = 9; TSH = 1.9 ± 0.2 μIU/ml). Neither plasma free fraction (25.0 ± 0.8%) nor apparent volume of distribution (0.72 ± 0.02 l/kg) in thyroidectomized rats differed from control values (26.4 ± 1.4%, 0.73 ± 0.02 l/kg). In ALD patients (four men; two women) tested with PTU (300 mg IV) before and after PTU therapy (150 mg b.i.d. orally) for 28 days, TSH rose from 3.6 ± 1.0 to 7.0 ± 2.6 μIU/ml (P = 0.03), but free PTU clearances rose in all patients (range 2.2% to 48.4%, P = 0.03). Free clearance before treatment was 1047 ± 131 and after treatment it was 1223 ± 139 ml/min; in 14 healthy subjects it was 1454 ± 86 ml/min. The alteration in clearance correlated positively (r = 0.91, P < 0.02) with the severity of disease as assessed by a composite clinical and laboratory index; in the more severely diseased patients there was the most alteration in both clearance and severity of ALD. There are two opposing events that determine net PTU disposition; biochemical hypothyroidism reduces PTU clearance, but improvement in hepatic function overcomes such an effect. The net increase in PTU free clearance reduces efficacy during long-term dosing. Clinical Pharmacology and Therapeutics (1982) 31, 559–563; doi:10.1038/clpt.1982.78

Heart rate responses during stimulation of the cardioaccelerator nerves were compared using Siamese and non-Siamese cats. The positive chronotropic responses of Siamese cats during activation of the cardioaccelerator nerves were significantly less than that observed for non-Siamese cats. There were no differences between the two cat populations when vasopressor and chronotropic responses to norepinephrine were cmpared. Comparison of atria from Siamese and non-Siamese cats using histochemical fluorescence indciated that there was a decreased norepinephrine content of the sympathetic nerves innervating the atria of Siamese cats.

The effects of chronic haloperidol treatment on presynaptic dopamine receptor sensitivity were studied on cat cardioaccelerator nerve terminals. Apomorphine and N, N-dimethyldopamine, two dopamine receptor agonists, caused inhibition of heart rate increase produced by postganglionic cardioaccelerator nerve stimulation. After termination of chronic haloperidol treatment, inhibition induced by apomorphine and N, N-dimethyldopamine was attenuated. The hypotensive and bradycardic effects of apomorphine did not change. Chronic haloperidol treatment did not alter the positive chronotropic responses of tyramine, isoproterenol or norepinephrine. These results suggest that presynaptic dopamine receptors on cat cardioaccelerator nerve terminals become subsensitive following withdrawal of chronic haloperidol treatment.