Hyperactivity induced by tetrahydroisoquinoline derivatives injected into the nucleus accumbens.

Several derivatives of tetrahydroisoquinoline were injected bilaterally into the nucleus accumbens of rat 2 h after a nialamide pretreatment and activity recorded in cages fitted with photocells. 1,2,3,4-Tetrahydroisoquinoline, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydro-6,7-dihydroxy-1-(3,4-dihydroxybenzyl)-isoquinoline (tetrahydropapaveroline) and 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused virtually no change in locomotor activity and 2-methyl-1,2,3,4-tetrahydroisoquinoline and 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline caused only modest hyperactivity responses. However, 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both shown to markedly increase activity in a dose-dependent manner. Of these two compounds, the 3-methyl-6,7-methylenedioxyderivatives was most active and equalled the effectiveness of dopamine. The responses to dopamine and to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline were both threshold at 3.125 mug and maximum at 50 mug. Both effects developed within 1-2 h and persisted for at least 6 h. The hyperactivity induced by dopamine was antagonised in a dose-dependent manner by haloperidol: propranolol and aceperone were without effect. Similar results were obtained for these blocking agents against the responses to 3-methyl-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline and 2-methyl-1,2,3,4-tetrahydroisoquinoline but aceperone and propranolol, in addition to haloperidol, were shown to inhibit the hyperactivity induced by 3-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline.     

Tetrahydroisoquinoline derivatives as possible Parkinson's disease-inducing substances

Parkinson's disease (PD) is believed to be induced by the interaction of genetic predisposition and environmental factors, and a type of neurotoxin is proposed to be one of the environmental factors. We designed and synthesized a molecule, 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) as a possible PD-eliciting neurotoxin and evaluated its characteristics relevant to PD. 1BnTIQ is an endogenous amine in the brain and the 1BnTIQ content increases in the patients with PD. Repeated administration of 1BnTIQ induced PD-like symptoms in monkeys and mice. 1BnTIQ was biosynthesized from 2-phenylethylamine and phenylacetaldehyde, which is a metabolite of 2-phenylethylamine, and used in in vivo and in vitro studies. 1BnTIQ inhibited [3H] dopamine uptake in HEK293 cells which stably express dopamine transporter. 1BnTIQ also inhibited NADH-ubiquinone oxidoreductase (complex I) in the mitochondrial respiratory chain. Next, we assessed 1BnTIQ neurotoxicity in the organotypic coculture of the ventromedial portion of the mesencephalon and striatum. 1BnTIQ decreased the dopamine content in the mesencephalon in both dose- and time-dependent manners and it irreversibly reduced the dopamine content. Furthermore, it caused morphological changes in tyrosine hydroxylase-positive cells in the mesencephalon and reduced the number of cells. 1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline (3'4'DHBnTIQ) is also an endogenous parkinsonism-inducing 1BnTIQ derivative. In vivo and in vitro studies revealed that 3'4'DHBnTIQ was O-methylated by soluble catechol-O-methyltransferase (COMT). The result that COMT inhibitor suppressed 3'4'DHBnTIQ neurotoxicity suggests that 3'4'DHBnTIQ is metabolically activated by COMT to exert toxic effects.     

Dopamine transporter and catechol-O-methyltransferase activities are required for the toxicity of 1-(3',4'-dihydroxybenzyl)-1,2,3, 4-tetrahydroisoquinoline

1-(3',4'-Dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline [3', 4'DHBnTIQ (1)] is an endogenous parkinsonism-inducing substance. It is taken up into dopaminergic neurons via the dopamine transporter, inhibits mitochondrial respiration, and induces parkinsonism in mice. We synthesized four derivatives [aromatized, N-methylated, N-methyl-aromatized, and O-methylated (2-5, respectively)] and studied the cellular uptake and cytotoxicity of 1-5, as well as the metabolism of 1. All except the O-methyl derivative (5) were specifically taken up by the dopamine transporter, but 1 was taken up most efficiently. Relative to 1, oxidation reduced v(max), N-methylation markedly increased K(m), and O-methylation eliminated the uptake activity. The cytotoxicity of 1-5 was examined in a mesencephalic cell primary culture. Compound 1 reduced cell viability by nearly 80% at 100 microM, but the other compounds had little or no effect on cell viability. In vivo and in vitro studies revealed that 1 was O-methylated by soluble catechol-O-methyltransferase (COMT). Aromatization and N-methylation of 1 were not observed. We found that dopamine transporter inhibitors and a COMT inhibitor each blocked the cytotoxicity of 1, indicating that uptake and O-methylation are both necessary for neurotoxicity. Thus, we consider that 1 is taken up into dopaminergic neurons via the dopamine transporter and then converted by COMT to 5, which has cytotoxic and parkinsonism-inducing activities.     

Synthese des 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisochinolins

Synthesis of 6,7-Dimethoxy-3-(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline The synthesis and chemical reactivity of 6,7-dimethoxy-3(3,4-dimethoxy-α-hydroxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline (I) are described.     

Evaluation of isomeric 4-(chlorohydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines as dopamine D-1 antagonists

The isomeric 4-(3-chloro-4-hydroxyphenyl)- and 4-(4-chloro-3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinolines, the N-methyl derivative of the 4-(4-chloro-3-hydroxyphenyl) isomer, and 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline were synthesized and evaluated for dopamine D-1 antagonist activity. The 4-(3-chloro-4-hydroxyphenyl) and the 4-(3-hydroxyphenyl) isomer possessed similar potencies as D-1 antagonists. Introduction of the N-methyl group enhanced potency about twofold. The "pharmacophore" for selective dopamine D-1 antagonist activity appears to be a tertiary 2-(3-hydroxyphenyl)-2-phenethylamine.     

Topographical assessment and pharmacological characterization of orofacial movements in mice: dopamine D(1)-like vs. D(2)-like receptor regulation

A novel procedure for the assessment of orofacial movement topographies in mice was used to study, for the first time, the individual and interactive involvement of dopamine D(1)-like vs. D(2)-like receptors in their regulation. The dopamine D(1)-like receptor agonists A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman) and SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine) each induced vertical jaw movements with tongue protrusions and incisor chattering. The dopamine D(1)-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) antagonised these responses, while the dopamine D(2)-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide) attenuated those to SK&F 83959 and released horizontal jaw movements. These findings suggest some role for a dopamine D(1)-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and for dopamine D(1)-like:D(2)-like receptor interactions, in the regulation of individual orofacial movement topographies in the mouse. This methodology will allow the use of knockout mice to clarify the roles of individual dopamine receptor subtypes in their regulation.     

Parkinsonism-preventing activity of 1-methyl-1,2,3,4-tetrahydroisoquinoline derivatives in C57BL mouse in vivo

1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), an endogenous parkinsonism-preventing substance, and its 5-, 6-, and 7-hydroxylated derivatives are reported to show in vitro neuroprotective activity against toxicity due to salsolinol in SH-SY5Y human neuroblastoma cells. In the present study, we tested the parkinsonism-preventing potential of these derivatives by means of the pole test in C57BL mice in vivo, and measured brain dopamine contents by liquid chromatography-tandem mass spectrometry. Parkinsonism was induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydroisoquinoline(MPTP), and pretreatment with any of the 1MeTIQ derivatives prevented its induction. 6-Hydroxy-1MeTIQ showed the greatest preventive activity. The amount of dopamine in the brain was reduced by MPTP treatment, and this reduction was suppressed by pretreatment with 1MeTIQ derivatives. These hydroxy-1MeTIQ derivatives may have potential for the treatment of Parkinson's disease as well as 1MeTIQ itself.     

Synthesis and pharmacological evaluation of some new tetrahydroisoquinoline derivatives inhibiting dopamine uptake and/or possessing a dopaminomimetic property

As shown by structure-activity relationship studies in 8-(substituted-amino)-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines, the most important structural requirement for a marked antidepressant action is the presence of an ureido, (alkoxycarbonyl)amino, or [(alkylamino)acyl]amino group attached to the isoquinoline skeleton in position 8. In one of the biological tests a significant difference was found between 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (nomifensine) and the new compounds synthesized. Nearly all compounds substituted in the amino group either decrease the spontaneous motility in mice or exert no effect on it. Two syntheses have been elaborated for the preparation of the compounds represented by the general formulas II-V where R1 = hydrogen, halogen, or methyl; Y = CONHR, OCOR, or CO(CH2)nNHR, in which R = alkyl or aralkyl or NHR = cyclic amine and n = 1-2. The syntheses start either from the corresponding 8-amino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines or from the corresponding noncyclized amino alcohols. Of the compounds, 4-(p-chlorophenyl)-8-[(ethoxy-carbonyl)amino]-2-methyl-1,2,3,4- tetrahydroisoquinoline was found to possess the highest activity.     

SK&F 83959 and non-cyclase-coupled dopamine D1-like receptors in jaw movements via dopamine D1-like/D2-like receptor synergism

This study compared the effects of the dopamine D1-like receptor agents SK&F 83959 (3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro- 1 H-3-benzazepine), which inhibits the stimulation of adenylyl cyclase, and A 68930 ([1R,3S]-1-aminomethyl-5,6-dihydroxy-3-phenyl-isochroman), a full efficacy agonist, in regulating jaw movements in the rat by synergism with dopamine D2-like receptor agonism. When SK&F 83959 and A 68930 were given in combination with quinpirole, there was a synergistic induction of jaw movements. Responsivity to SK&F 83959 + quinpirole was antagonised by the dopamine D1-like receptor antagonists SCH 23390 ([R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-ben zaz epine) and BW 737C ([S]-6-chloro-1-[2,5-dimethoxy-4-propylbenzyl]-7-hydroxy-2-methyl- 1,2,3,4-tetrahydroisoquinoline); synergism was antagonised also by the dopamine D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-++ +methyl-aminobenzamide). Responsivity to A 68930 + quinpirole was enhanced by low doses of SCH 23390, BW 737C and YM 09151-2, and antagonised by higher doses of SCH 23390 and YM 09151-2. These results implicate a novel, dopamine D1-like receptor that is coupled to a transduction system other than/additional to adenylyl cyclase, and suggest that its functional role extends to the regulation of jaw movements by synergistic interactions with dopamine D2-like receptors.     

Catalepsy-associated behavior induced by dopamine D1 receptor antagonists and partial dopamine D1 receptor agonists in squirrel monkeys

Observational procedures were used to compare the behavioral effects of dopamine D₁ receptor antagonists and partial dopamine D₁ receptor agonists in squirrel monkeys. The dopamine D₁ receptor antagonists SCH 39166 ((−)-tran-6- 7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo(d)naphtho-(2,1-b)azepine) and BW 737C89 ([S]-6-chloro-1[2,5-dimethoxy-4-propylbenzyl]- hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline) produced dose-related increases in the duration of static and unusual postures, indicative of catalepsy. R-SKF 38393 (R(+)-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) and SKF 75670 (7,8-dihydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine), which are considered partial dopamine D₁ receptor agonists, also consistently produced dose-related increases in catalepsy-associated behavior and had effects comparable in magnitude to those of dopamine D₁ receptor antagonists. In contrast, the higher efficacy D₁ agonists SKF 81297 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-[1H]-3-benzazepine) and SKF 82958 (6-chloro-7,8-dihydroxy-1-phenyl-2,3,4, 5-tetrahydro-3-allylp-[1H]-3-benzazepine) did not produce catalepsy-associated behavior at any dose tested. The results indicate that dopamine D₁ agonists differ with respect to cataleptogenic activity, possibly reflecting differences in intrinsic activity.     

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.     

莲子心生物碱的研究——Ⅳ.莲心碱的全合成

本文报导了莲心碱(Ⅰ)全合成的研究。(1)合成了1-(3′-溴-4′-苄氧基)苄基-2-甲基-6,7-二甲氧基-1,2,3,4-四氢异喹啉(Ⅷ)和1-(4′-苄氧基)苄基-2-甲基-6-甲氧基7-羟基-1,2,3,4-四氢异喹啉(XV).(2)1-(3′-溴-4′-苄氧基)苄基-6,7-二甲氧基-1,2,3,4-四氢异喹啉(Ⅵ)和1-(4′-苄氧基)苄基-6-甲氧基-7-乙酰氧基-1,2,3,4-四氢异喹啉(ⅩⅢ)借d-和1-DPT-酒石酸各自拆分为其对映体。D-(-)-Ⅵ和L-(+)-Ⅵ以甲酸和甲醛甲基化分别生成D-(-)-Ⅷ和L-(+)-Ⅷ。D-(+)-;ⅩⅢ和L-(-)-ⅩⅢ经N-甲基化后再进行水解卽得D-(-)-ⅩⅤ和L-(+)+ⅩⅤ。(3)D-(-)-Ⅷ和D-(-)-ⅩⅤ在吡啶中有铜粉和碳酸钾存在下进行Ullmann反应,反应物经氧化鋁柱层析可分得一油状物,此油状物经盐酸水解得黄色无定形固体,后者与过氯酸生成过氯酸盐结晶,其理化性质均与天然莲心碱过氯酸盐相同。(±)-Ⅷ和(±)-ⅩⅤ在相似的条件下缩合则生成(±)-莲心碱。     

Synthesis of 1-substituted analogues of trimetoquinol possessing differential and selective beta-adrenergic properties.

The synthesis of the 1,1-disubstituted tetrahydroisoquinoline analogues, 1-methyl-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2) and 1-benzyl-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3), is described. The profile of beta-adrenergic activity for these analogues was determined and compared to that of trimetoquinol (1) in isolated guinea pig atrial, tracheal, and rat adipocyte preparations. Unexpected selective beta1-blocking activity in guinea pig trachea was noted with analogue 3. With the exception of 2 in guinea pig atria, 2 and 3 did not possess any beta-stimulant activity. Substitution at the 1 position of trimetoquinol (1) has revealed qualitative differences in beta-adrenergic activity.     

Synthesis and biological evaluation of fragmented derivatives of tetrahydroisoquinolines. 2. Trimetoquinol studies.

The synthesis of N-(3',4',5'-trimethoxyphenylethyl)-3,4-dihydroxyphenylethylamine (2) and 1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (1) is presented. Comparative pharmacological effects of the optical isomers of 1 and compound 2 are reported in guinea pig atria, rat adipose tissue, guinea pig trachea, and guinea pig aortic strip preparations. In the beta-adrenoreceptor preparations, (-)-1 was shown to be more potent than (+)-1 or 2. Racemic 1 and 2 were shown to have equal alpha-antagonist properties in the inhibition of norepinephrine-induced contractions of guinea pig aorta.     

Metabolism and penetration through blood-brain barrier of parkinsonism-related compounds. 1,2,3,4-Tetrahydroisoquinoline and 1-methyl-1,2,3,4-tetrahydroisoquinoline.

14C-Labeled 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) were synthesized, and their metabolism and tissue distribution were studied. Both compounds showed similar metabolic patterns. In 24 hr after po administration (50 mg/kg) to rats, 76% of TIQ and 72% of 1MeTIQ were excreted unchanged, and 2.7 and 8.7% were excreted as the 4-hydroxyl derivatives, 4-hydroxy-TIQ and 4-hydroxy-1MeTIQ, respectively. Small amounts of N-methylated metabolites, 2-methyl-TIQ (0.4%) and 2-methyl-1MeTIQ (0.7%) were detected. Isoquinoline (2.5%) also was found as a metabolite of TIQ and 1-methyl-3,4-dihydroisoquinoline (1.0%) was found as a metabolite of 1MeTIQ. The concentration of labeled compounds in the brain was about 4.5-fold higher than the blood concentration at 4 hr after dosing, and over 90% was unchanged TIQ or 1MeTIQ. These data indicated that TIQ and 1MeTIQ easily passed through the blood-brain barrier and were concentrated in the brain. Thus, it appears that TIQ and 1MeTIQ as endogenous or exogenous amines may accumulate in the brain and may be related to the onset of Parkinson's disease.     

1-methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain

The effect of single and multiple administration of the neurotoxic pesticide, rotenone, and the potentially neuroprotective compound, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), on the concentration of dopamine and its metabolites (homovanillic acid-HVA, 3,4-dihydroxyphenylacetic acid-DOPAC, and 3-methoxytyramine-3-MT)) in three brain areas was studied by high-performance liquid chromatography (HPLC) with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of dopamine metabolites to dopamine. In addition, the effect of rotenone on mortality and general behavior of rats was investigated. We have found that the neurotoxic pesticide, rotenone, administered in a single dose (12 mg/kg s.c.) did not produce evident behavioral or biochemical effects. In contrast, repeated administration of rotenone in doses (12-15 mg/kg) causing abnormalities in general behavior, produced considerable mortality and dramatic increases in dopamine metabolism, which may be ascribed to an increase in the oxidative pathway. Interestingly, it depressed the concentration of the extracellular dopamine metabolite, 3-MT. These behavioral and biochemical changes were effectively counteracted by administration of 1MeTIQ before each dose of rotenone. In summary, we demonstrated that multiple systemic rotenone injections are strongly toxic, and induce alterations of cerebral dopamine metabolism, and that 1MeTIQ may be considered as a potential protective agent against environmental factors affecting the function of the dopaminergic system.     

1-［1-(6-甲氧基-2-萘基)乙基］-2-(4-硝基苄基)-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐的光降解产物研究

研究1-［1-(6-甲氧基-2-萘基)乙基］-2-(4-硝基苄基)-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐(编号P91024)遇光后颜色变暗的光降解产物。采用HPLC-MS及波谱分析鉴定光降解产物的化学结构，并经有机反应合成对照验证。P91024光降解的3个主要产物分别为溴化N-(4-硝基苄基)-6,7-二甲氧基-3,4-二氢异喹啉、1-［1-(6-甲氧基-2-萘基)乙基］-6,7-二甲氧基-1,2,3,4-四氢异喹啉和2-异丙基-6-甲氧基萘。     

Neuroprotective effects of echinacoside in the mouse MPTP model of Parkinson's disease

In the present study, we investigated the neuroprotective effects of echinacoside, a phenylethanoid glycoside extracted from the medicinal Chinese herb Cistanches salsa, against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic toxicity. We confirmed that exposure to MPTP in mice leads to permanent behavioral deficits and depletion of dopamine and its metabolites. When administered prior to MPTP, echinacoside reduced behavioral deficits, increased striatal dopamine and dopamine metabolite levels, reduced cell death, and led to a marked increase in tyrosine hydroxylase expression relative to mice treated with MPTP alone. In addition, pre-treatment with echinacoside significantly reduced caspase-3 and caspase-8 activation in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in cerebellar granule neurons. Taken together, these findings suggest that echinacoside improves the behavioral and neurochemical outcomes in MPTP mice model of Parkinson's disease and inhibits caspase-3 and caspase-8 activation in cerebellar granule neurons, making the compound an attractive candidate treatment for various neurodegenerative disorders, including Parkinson's disease.     

Actions of two dopamine derivatives at adreno- and cholinoceptors.

Salsolinol (1)and 6,7-dihydroxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (2) were synthesized and their effects at adreno- and cholinoceptors investigated both in vivo and in vitro. Both 1 and 2 produced agonist effects at cholinoceptors and alpha- and beta-adrenoceptors. Neuromuscular blocking actions were evident in vitro. Compound 2 exhibited anticholinesterase properties both in vivo and in vitro. These results indicate that dopamine derivatives of this type exhibit not only sympathomimetic activity but also complex actions at cholinoceptors.     

Synthesis and biological activity of 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines.

Various 2- and 4-substituted 6,7-dihydroxy-1,2,3,4-tetrahydroisquinolines were synthesized and evaluated as substrates and inhibitors of catechol O-methyltransferase (COMT). In addition, these compounds were tested for their ability to release norepinephrine-3H from mouse hearts in vivo. Methyl substituents in the 2 and/or 4 positions of 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline had little effect on the interaction of these molecules with COMT. In general, the substrate kinetic (Km, Vmax) and inhibitory kinetic (Kis) properties toward COMT were similar for each of these compounds. In contrast, norepinephrine depleting activity showed more strict structural requirements. Methyl substituents in the 2 or 4 positions of the parent compound, 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, eliminated the norepinephrine depleting activity. The interesting exception was 6,7-dihydroxy-2,2-dimethyl-1,2,3,4-tetrahydroisoquinolinium iodide, which was found to be more active than the parent molecule as a depleter of norepinephrine from mouse hearts.