Neurochemical and behavioral evidence for a selective presynaptic dopamine receptor agonist.

A new dopamine analog, 6,7-dihydroxy-2-dimethylaminotetralin (TL-99), was compared to apomorphine in three tests of dopaminergic function in the central nervous system. The tests, performed on rats, included production of changes in locomotor activity (involving both presynaptic and postsynaptic receptors), inhibition of dopa accumulation (quantifying presynaptic receptor activity), and the rotation model (quantifying postsynaptic receptor activation). Apomorphine was efficacious at both presynaptic and postsynaptic receptors, whereas TL-99 was much more efficacious at the presynaptic receptor. This result indicates not only that differences exist between presynaptic and postsynaptic dopamine receptors, but also that these differences may be exploited in the design of selective dopamine agonists.

Ergoline congeners as potential inhibitors of prolactin release. 2.

In our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared one indolealkylamine and several 2-aminotetralin derivatives. These congeners have been evaluated for inhibition of prolactin release in vivo. One congener, 5,8-dihydroxy-2-dimethylaminotetralin, and the drug M-7 significantly inhibited prolactin secretion.

Ergoline congeners as potential inhibitors of prolactin release. 3. Derivatives of 3-phenylpiperidine.

In a continuation of our attempts to elucidate the prolactin release inhibiting pharmacophore within the ergoline structure, we have prepared several derivatives of 3-phenylpiperidine. These congeners have been evaluated for inhibition of prolactin release in vivo and are for the most part inactive.

N-Alkyl derivatives of (+/-)-alpha-methyldopamine.

A series of N-alkylated alpha-methyldopamine derivatives has been prepared for comparison of their biological effects with those of semirigid dopamine congeners derived from 2-aminotetralin systems. All of the alpha-methyldopamine derivatives were inert as dopaminergic agonists in a variety of animal assays, both centrally and peripherally, although certain compounds produced powerful and prolonged locomotor hyperactivity on intra-accumbens injection in mice, by indirect mechanism(s). A rationalization, based upon conformational analysis, is presented for the lack of direct dopaminergic agonist activity of alpha-methyldopamine derivatives.

Comparison of biological effects of N-alkylated congeners of beta-phenethylamine derived from 2-aminotetralin, 2-aminoindan, and 6-aminobenzocycloheptene.

Three series of bicyclic, semirigid congeners of beta-phenethylamine have been prepared for evaluation of the effect of ring size (and of concomitant conformational variation) on biological activity in a variety of assays for adrenergic and dopaminergic actions. Pharmacologic activity was associated with 2-aminotetralin and 2-aminoindan derivateves, but was not found with 6-aminobenzocycloheptene derivatives. Noteworthy is the ability of several aminotetralins and aminoindans to increase the hot-plate reaction time without eliciting dopaminergic effects. This action was not blocked by pretreatment with naloxone.

Sedative and analgesic actions of methoxylated 2-aminotetralins; involvement of alpha 1- and alpha 2-adrenoreceptors.

Three 5,8-dimethoxylated derivatives of 2-aminotetralin (2-AT) were compared with clonidine, methoxamine and phenylephrine in tests for sedation (inhibition of exploratory activity) and analgesia. In both tests the 2-AT derivatives were less potent than clonidine, but more potent than methoxamine or phenylephrine. Antagonism of the 2-AT derivative, DR-31, and clonidine by yohimbine in both tests argues for the involvement of alpha 2-adrenoreceptors in the mediation of these behavioral effects. alpha 1-Adrenoreceptors may also mediate an inhibition of exploratory activity since the inhibition induced by methoxamine was antagonized by phenoxybenzamine (POB) but not by yohimbine. The methoxylated 2-AT derivatives, which have previously been shown to exert potent peripheral alpha 1-agonism are now demonstrated to have sedative and analgesic effects characteristic of central alpha 2-adrenergic stimulation.

Dopaminergic effects of non-hydroxylated rigid analogs of apomorphine.

A series of rigid analogs of apomorphine lacking aromatic hydroxyl substitutents were evaluated for dopaminergic properties. Three compounds, N-methyl-N-propyl-2-aminotetralin (Me-Pr-2-AT), N-N-dipropyl-2-aminotetralin (Di-pr-2-AT) and N,N-dipropyl-2-aminoindane (Di-Pr-2-AI) induced emesis in dogs, contralateral circling in unilaterally lesioned rats, and inhibited prolactin secretion. The induced circling responses, however, were attenuated by prior treatment with alpha-methyl-p-tyrosine methyl ester (AMPTME) and the compounds were weak inhibitors of 3-H-dopamine binding in calf caudate homogenates. The possibility that these agents may be metabolically activated in vivo is discussed.

NMR study of amphetamines using europium shift reagents.

Amphetamine and certain of its methoxylated derivatives show a high degree of interaction with NMR shift reagents of the type tris (1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedione)europium(III). The shifts are not accompanied by appreciable line broadening, and both the aliphatic and aromatic protons can be resolved. The strong interaction between amine and shift reagent diminishes rapidly as the amine function is alkylated. For derivatives containing ortho-methoxyl groups, a weaker interaction with this functionality also becomes evident as the amine is alkylated. The stereospecificity of the shifting process was investigated by employing tris[3-(trifluoroacetyl)-d-camphorato]europium(III), a chiral shift reagent, with stereochemically pure enantiomers and known enantiomeric mixtures. Although certain (R)-enantiomers showed greater downfield C-methyl groups shifts, these shift differences from the corresponding (S)-enantiomers were small and not well resolved.

Effect of alpha-methyltryptamine on spontaneous activity in mice.

A standard dose of 10 mg/kg (48 mu mole/kg) of (+/-)-alpha-methyltryptamine (AMT) induced a significant and long lasting increase in spontaneous activity in mice. Pretreatment of mice with either pimozide or alpha-methyl-para-tyrosine methyl ester HCl (AMPT) prevented the activity increase induced by AMT. In similar trials, methysergide or para-chlorophenylalanine (PCPA) were also found to antagonize the development of hyperactivity following a standard dose of AMT. The results suggest that both endogenous dopamine and serotonin many participate in the hyperactivity induced by AMT.

Sympathetic nerves exert a chronic influence on the intact vasculature that is age related.

The hypothesis of this study is that the chronic presence of intact sympathetic innervation influences the structure, and thereby function, of the rabbit ear vascular bed, and that this influence may be age related. Therefore we examined the effect of chronic sympathetic denervation on vascular resistance of the rabbit ear nine to ten weeks after unilateral superior cervical ganglionectomy. Two age groups were studied: growing juvenile rabbits denervated at 4 weeks of age and adult rabbits denervated at 16 weeks. We assessed the flow-pressure (resistance) curves of the chronically denervated and contralateral innervated isolated rabbit ears during maximum dilation. The flow-pressure curve was significantly shifted downward in the denervated compared to the contralateral innervated ears of juvenile rabbits operated on at 4 weeks (p less than 0.001) but was not different in adult rabbits operated on at 16 weeks. These results support the concept that the sympathetic nerves chronically influence blood vessel properties in growing animals, apart from their acute effect on vasomotor tone.

The trophic influence of sympathetic nerves on rabbit ear vasculature is absent in coarctation hypertension.

We recently investigated the effect of chronic sympathetic denervation on the intact ear vasculature of normotensive rabbits and found an important long-term or trophic influence of sympathetic nerves on vascular structural properties. To determine the effect of coarctation hypertension on this relationship, we studied 12 wk old rabbits 8 wk after a unilateral superior cervical ganglionectomy and induction of coarctation hypertension. Successful denervation was demonstrated by a shift of the norepinephrine dose-response curve to the left in the denervated ears as well as a decreased threshold (p less than 0.05), an increased slope (p less than 0.02) and a decreased M50 (p less than 0.01) (the concentration of norepinephrine that produced 50% of the maximal vasoconstrictor response to norepinephrine). The flow-pressure curves of the denervated compared to the innervated ears at maximal dilation (used as a functional assessment of structural alterations) did not differ. The maximal pressor responses to vasopressin and barium chloride (used as an indication of smooth muscle mass) also did not differ. These results suggest that sympathetic innervation does not importantly influence blood vessel structure during coarctation hypertension in contrast to the changes we previously found in normotensive rabbits.

Aminotetralin analogs of methoxamine as potential hypertensive agents.

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.

Centrally mediated hypotension and bradycardia induced by an aminotetralin derivative: TL-68.

An aminotetralin derivate, N,N-dipropyl-2-amino-1,2,3,4-tetrahydronaphthalene (TL-68) induced a prolonged decrease in blood pressure and heart rate when administered i.v. in anesthetized cats. The compound inhibited the blood pressure and heart rate responses induced by central stump stimulation of the sciatic nerve indicating inhibition of sympathetic transmission. TL-68 caused a weak inhibition of the positive chronotropic response induced by stimulation of the cardioaccelerator nerve. When comparatively low doses of TL-68 were injected into the left vertebral artery, a considerable dose-dependent decrease in blood pressure and heart rate developed. The same doses had only small or negligible effects on blood pressure and heart rate when given intravenously. When TL-68 was injected into a lateral cerebral ventricle of unanesthetized rats, a significant hypotension and bradycardia was observed which could be prevented by prior intraventricular injection of phentolamine. The results suggest that this compound exerts its effect through a central mechanism of action, perhaps by stimulation of alpha-adrenoreceptors.

Inhibition of apomorphine-induced behaviors by derivatives of 2-amino-1, 2, 3, 4-tetrahydronaphthalene.

In order to elucidate the pharmacological properties of a series of 1-phenyl-2-aminopropane and 2-amino-1, 2, 3, 4-tetrahydronaphthalene derivatives, their ability to inhibit a number of apomorphine-induced behaviors was investigated. Several members of the series under study were potent inhibitors of apomorphine-induced pecking behavior in pigeons, emesis in dogs, and gnawing in rats. In addition, these compounds were able to inhibit responding in self-stimulating rats and to a lesser degree counteracted the depression of the linguomandibular reflex induced by 5, 6-dihydroxy-2-dimethylamino-1, 2, 3, 4-tetrahydronaphthalene (M-7) in the cat. The most effective member of the experimental compounds was N-methyl-5, 8-dimethoxy-2-amino-1, 2, 3, 4-tetrahydronaphthalene; however, neither this material nor any of the related structures were able to inhibit apomorphine-induced rotational behavior in substantia nigra lesioned rats. The possibility that the more effective members of the experimental series are able to inhibit certain apomorphine-induced behaviors by stimulation of central alpha adrenergic receptors is discussed.