Synthesis and biological evaluation of a tetrahydroisoquinoline derivative possessing selective beta2-adrenergic agonist activity.

This paper reports the synthesis of 4-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (2) and 2-(3,4-dihydroxyphenyl)-3-(3,4,5-trimethoxyphenyl)propylamine (3). The biological activity of these agents relative to that of trimetoquinol (1) in guinea pig atria and guinea pig trachea is reported. The relative activities in relaxation of guinea pig trachea is 1 greater than 2 greater than 3 while in the chronotropic response in guinea pig atria the relative order of activity is 1 greater than 3 greater than 2.     

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.     

Selective and potent beta 2-adrenoceptor agents within the tetrahydroisoquinoline class: effect of methyl substitution at the benzylic carbon of the 1-(3,4,5-trimethoxybenzyl) group of trimetoquinol

A systematic series of methyl (2 and 3) and dimethyl (4) analogues of trimetoquinol (1) were synthesized and evaluated for their beta 1 (atria) and beta 2 (trachea) and adrenoceptor activities. Structural assignments for the erythro (2) and the threo (3) diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline were based on NMR spectra of the 6,7-dibenzyl precursors 15 and 16, respectively, and on the synthetic derivatives of cis- and trans-13-methyl-2,3-bis(benzyloxy)-9,10,11-trimethoxytetrahydroprotoberberine (18 and 17). The rank order of beta 2-agonist activity for these compounds was 3 greater than 1 greater than 2 greater than 4. The rank order of activity as beta 1 agonists on the guinea pig atria is 1 greater than 3 greater than 2, and 4 was inactive. The methylated analogues show selectivity for beta 2 receptors in our preliminary pharmacological studies. The threo isomer 3 is the most potent and selective beta 2 stimulant reported to date in the tetrahydroisoquinoline class.     

Bronchoselective actions of a new series of trimetoquinol analogues

In selected beta 1- (guinea pig atrial) and beta 2- (guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-alpha-methylbenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (alpha-methylTMQ), alpha-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5-trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-alpha-methylTMQ greater than (+/-)-TMQ greater than ISO greater than erythro-alpha-methylTMQ greater than N-methylTMQ greater than alpha-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the alpha-methylated TMQ analogues were partial agonists in this beta 2-system. In atria, the rank order of beta 1-potency was ISO greater than (+/-)-TMQ greater than threo-alpha-methylTMQ greater than N-methylTMQ = erythro-alpha-methylTMQ. Maximal chronotropic effects of all compounds, with the exception of threo-alpha-methylTMQ, were similar to ISO in this preparation. Both alpha-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agonists in this beta 1-system. The ratio of beta 2 : beta 1 selectivity (trachea vs. atria), relative to ISO for threo-alpha-methylTMQ, erythro-alpha-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO greater than threo-alpha-methylTMQ = TMQ greater than erythro-alpha-methylTMQ, the comparative beta 2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-alpha-methylTMQ, threo-alpha-methylTMQ and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the alpha-carbon of the 1-(3,4,5-trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-alpha-methylTMQ and erythro-alpha-methylTMQ were more beta 2-selective than (+/-)-TMQ.     

Evaluation of the optical isomers of tetrahydroisoquinolines in rat adipose tissue and guinea pig aorta

The adrenoceptive properties of tetrahydroisoquinoline (THI) stereoisomers were evaluated in rat adipose tissue and guinea pig aorta, in vitro. The rank order of lipolytic activity observed for the more potent S-(?)-isomers of the THI's tested was trimetoquinol > 1-benzyl-6,7-dihydroxy-1,2,3,4-THI > tetrahydropapaveroline > salsolinol. The stereoisomers of trimetoquinol and racemic 1-benzyl-6,7-dihydroxy-1,2,3,4-THI were found to be equally active as competitive antagonists of noradrenaline-induced contraction of guinea pig aortic strips.     

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.     

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.     

Synthesis and beta-adrenoceptor activity of the erythro and threo isomers of substituted alpha-hydroxytrimetoquinol.

The synthesis and pharmacological activity of erythro and threo isomers of 1-(3',4',5'-trimethoxy-alpha-hydroxy-benzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, 2 and 3, are reported. The structural assignments of 2 and 3 are based upon NMR spectra of the 6,7-dibenzyl precursors, 6 and 10, and of the synthetic derivatives of 13alpha- and 13beta-hydroxy-2,3-(dibenzyloxy)-9,10,11-trimethoxytetrahydroprotoberberine, 8 and 12, respectively. The erythro isomer 2 was a more potent beta-adrenoceptor stimulant than the threo isomer 3 in guinea pig atrial, guinea pig tracheal, and rat adipocyte preparations. The differential activity of these compounds on lipolysis was favorably correlated to changes in the stimulation of adenylate cyclase activity and cAMP accumulation in rat adipocytes.     

Synthesis and pharmacological evaluation of 1-oxo-2-(3-piperidyl)-1,2,3,4- tetrahydroisoquinolines and related analogues as a new class of specific bradycardic agents possessing I(f) channel inhibitory activity

A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were prepared and evaluated for their bradycardic activities in isolated right atrium and in anesthetized rats. (+/-)-6,7-Dimethoxy-2-[1-[3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl]-1,2,3,4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore, methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against I(f) currents. Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence on blood pressure after oral administration. The compound also showed inhibition of I(f) currents (IC(50) = 0.32 muM) in guinea pig pacemaker cells.     

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.     

Influence of substituted tetrahydroisoquinolines and catecholamines on lipolysis, in vitro. II. Stereoselectivity

Utilizing glycerol release as an index of lipolysis in rat epididymal fat tissue, intrinsic activity and affinity (pD₂ values) constants were calculated for various tetrahydroisoquinoline (THI) and catecholamine derivatives. Differences were noted in the pD² values and to a lesser degree in the intrinsic activity constants of the d-l-isomers and deoxy derivatives of the agonists studied. In all cases, the l-isomers proved to be more active than the d-isomers or deoxy derivatives in the release of glycerol from adipose tissue, in vitro. Significant differences in the pD₂ values for the more potent l-isomers were calculated and the rank order was observed to be 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI > isoproterenol > norepinephrine ≥ 1-benzyl-6,7-dihydroxy-1,2,3,4-THI. The deoxy derivatives of isoproterenol and norepinephrine possessed nearly identical pD₂ values to their respective d-isomers. N-isopropyldopamine and dopamine, however, were unable to elicit a maximum lipolytic response and did not possess equivalent intrinsic activity constants to d-isoproterenol and d-norepinephrine. Propranolol inhibited the lipolysis induced by 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI and norepinephrine in a competitive manner, whereas a noncompetitive inhibition was observed in the presence of the alpha-antagonist, phentolamine. The activity-differences for the isomers of 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI (795-fold) and isoproterenol (316-fold) were clearly greater than the isomeric-activity differences observed for norepinephrine (100-fold) and 1-benzyl-6, 7-dihydroxy-1,2,3,4-THI (25-fold). These results indicate: (a) that the THI derivatives which do not possess an alcoholic (μ-hydroxyl) group on the ethylamino-side chain are potent lipolytic agonists, and (b) that the tetrahydroisoquinoline derivatives act at a receptor system in adipose tissue similar, if not identical, to the interaction observed with norepinephrine. It may be suggested, therefore, that the μ-hydroxyl group is not a necessary requirement for potent lipolytic activity as previously believed.     

Determination of trimethoquinol in plasma by electrochemical detection after HPLC separation

A high pressure liquid chromatographic method with internal analogue standardization for the determination of trimethoquinol (1-1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoq uinoline hydrochloride) in plasma is described. The method comprises extraction from plasma at pH 9 with ethyl acetate, back-extraction into phosphoric acid and quantification after HPLC separation using a reverse phase by means of electrochemical (reductive) detection after electrochemical preoxidation. When using 5 ml plasma the lower limit of detection is 40 pg/ml. Under routine conditions the limit of determination is determined to be 0.1 ng/ml. The variation coefficients drop from about 7% in the low range to about 4% at 5 ng/ml. The determination of trimethoquinol is not impaired by its monomethylated metabolites.     

买麻藤有效成分的研究

买麻藤系买麻藤科植物小叶买麻藤Gnetum parvifolium(Warb.)C.Y.Gheng别名山花生,药用其藤茎,福建省分布较广,资源丰富,民间用于治疗支气管炎。近年来,我们对买麻藤进一步临床验证,证明对老年慢性支气管炎有较好疗效。为了寻找其有效成分,进行了化学分离和药理研究。 取福建产的买麻藤粗粉60kg,以乙醇提取,得醇浸膏。以少量热水处理浸膏多次,合     

The chromatographic data in QSAR assay of TIQs derivatives with beta2-adrenergic activity

We performed QSAR analysis of beta2-adrenergic activity and chromatographic data of 4,6,8-trihydroxy-, 6,7-dihydroxy- and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives. TLC plates (silica gel NP 60F(254) and silica gel RP2 60F(254) silanised precoated), impregnated with solutions of analogues of the selected amino acids were used as beta2-agonistic and antagonistic interaction models. QSAR analysis of the beta2-adrenergic activity and the chromatographic data of the solutes were made. A correlation between biological data and behaviour of the examined compounds in a chromatographic modifiable environment (S1-S3) was investigated by the linear regression analysis method.     

Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.     

5-fluoro- and 8-fluorotrimetoquinol: selective beta 2-adrenoceptor agonists

The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).     

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.     

Discovery of antiglioma activity of biaryl 1,2,3,4-tetrahydroisoquinoline derivatives and conformationally flexible analogues

Cultured rat astrocytes and C6 rat glioma were used as a differential screen for a variety of 1,2,3,4-tetrahydroisoquinoline (THI) derivatives. Compound 1 [1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol hydrochloride] selectively blocked the growth of C6 glioma leaving normal astrocytes relatively unaffected. The potential for clinical utility of 1 was further substantiated in human gliomas and other tumor cell lines. Preliminary SAR of this activity was characterized by synthesis and testing of several THI and conformationally flexible variants.     

The blockade of alpha 2-adrenoceptors by the PNMT inhibitaor SK&F 64139

Three tetrahydroisoquinolines were tested for activity on central alpha 2-adrenoceptors by determining their ability to inhibit [3H]clonidine binding to rat cerebral cortical membrane homogenates. The compounds included the PNMT inhibitors SK&F 64139 (7,8-dichloro-1,2,3,4-tetrahydroisoquinoline) and SK&F 29661 (1,2,3,4-tetrahydroisoquinoline 7-sulfonamide) as well as SK&F 72223 (5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline) a structural analogue inactive as a PNMT inhibitor. SK&F 64139 and SK&F 72223 but not SK&F 29661 inhibited [3H]clonidine binding. Studies in the isolated guinea pig atrium confirmed that SK&F 64139 and SK&F 72223 are alpha 2-adrenoceptor antagonists.     

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.