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D R Feller

Publications and source records attributed to D R Feller.

At least 37 records · Page 2Linked to original sources
PubMed1996

Pharmacological study of atypical beta-adrenoceptors in rat esophageal smooth muscle.

The chemical specificity for the beta-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective beta-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-but an-2-ol] and the beta-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (+/-)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [(R* R*)-(+/-)-4-[2'-2-hydroxy 2-(3-chlorophenyl)ethylamino]propyl] phenoxyacetic acid] (8.16) = ICID7114 [(S)-4-(2-hydroxy- 3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) > or = (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3',5'-diiodo-4'-methoxybenzyl)-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1- (3',4',5'-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'- trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.56) > or = (-)-noradrenaline (6.46) > or = (-)-adrenaline (6.36) > (+/-)-noradrenaline (6.24) > (+/-)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- > > (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 microM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical beta/beta 3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical beta/beta 3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical beta/beta 3-adrenoceptors. (-)-Trimetoquinol was as potent as (-)- isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.

Adrenergic beta-1 Receptor Antagonists↗
PubMed1996

Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes.

The beta-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily beta 1 (atria)-, beta 2 (trachea)- and atypical beta/beta 3 (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which was 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respectively. (+/-)-Trimetoquinol was equally or slightly less active than (-)-trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoquinol exhibited differential activation of beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta 3-adrenoceptors than those tissues containing beta 1- and beta 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta 1-adrenoceptors. Pharmacological properties of the compounds on rat beta 3-adrenoceptors expressed in Chinese hamster ovary (CHO) cells were consistent with results observed in functional assays. 3',5'-Diiodotrimetoquinol possessed the greatest potency for activation of adenylyl cyclase. Rank order of affinity for rat beta 3-adrenoceptor was 3'-iodotrimetoquinol = 3',5'-diiodotrimetoquinol > (+/-)-trimetoquinol > (-)-isoprenaline. These results suggest that 3',5'-diiodotrimetoquinol is a promising drug for further chemical modification in the development of selective beta 3-adrenoceptor ligands.

Adipose Tissue, Brown↗
PubMed1996

Convergence of three steroid receptor pathways in the mediation of nongenotoxic hepatocarcinogenesis.

The mechanisms by which peroxisome proliferators are able to regulate metabolic processes such as fat metabolism, while at the same time creating an environment for the development of hepatocellular carcinomas, is a central issue in the non-genotoxic carcinogenesis field. The convergence of two members of the steroid receptor family (peroxisome proliferator-activated receptor, PPAR; and retinoid X receptor, RXR) has provided strong support for an oxidative stress component in this carcinogenesis process, but has yet to define clearly a pathway for the classical tumor promotion events associated with peroxisome proliferation. The findings presented here integrate a third member of the steroid receptor family into this process and suggest a novel autocrine loop and mechanism for creating both oxidative stress and tumor promotion. A central regulatory component in this pathway is farnesol which has recently been shown to induce transcription mediated by the steroid receptor family member, farnesoid X receptor (FXR). In this report, it is clearly demonstrated that farnesol can also upregulate the transcriptional events of PPAR, but most likely through a different farnesoid metabolite, resulting in the regulation of an entirely different set of genetic components. Deregulation of the activities of these receptors offers a provocative mechanism for explaining the hepatocarcinogenic effects of peroxisome proliferators in chronically treated rodents.

Acyl-CoA Oxidase↗
PubMed1996

Differential eudismic ratios in the antagonism of human platelet function by phenoxy- and thiophenoxyacetic acids.

The antilipidemic drug clofibric acid (CPIB) exhibits antiplatelet effects. In order to examine the role of enantioselectivity and hydrophobicity, the mono(desmethyl) enantiomers of 2-(4-chlorophenoxy)propanoic acid (CPPA), related butanoate homologs, 2-(4-chlorophenoxy)butanoic acid (CPBA), thioether relatives, 2-(4-chlorothiophenoxy)propanoic acid (CTPA) and corresponding butanoate homologs, 2-(4-chlorothiophenoxy)butanoic acid (CTBA) were studied. All compounds inhibit prostaglandin-dependent human platelet aggregation and serotonin secretion induced by ADP. For the phenoxy acid series, (+)-(R)-CPPA is 5-fold more potent than either (-)-(S)-CPPA or CPIB giving a rank order potency of (+)-(R)-CPPA > (+)-(R)-CPBA > (-)-(S)-CPPA > (-)-(S)-CPBA. With the exception of (-)-(S)-CTPA, all thiophenoxy acid enantiomers are less potent than their respective phenoxy acid isomers [(+)-(R)-CTPA > (-)-(S)-CTPA > (+)-(R)-CTBA > (-)-(S)-CTBA]. The same rank order of potencies are observed against responses induced by arachidonic acid (AA) with the exception of CPIB which is inactive. However, inhibition of thrombin-induced [3H]-AA release by phenoxyacetic acids is not stereoselective but correlates with hydrophobicity.

Arachidonic Acid↗
PubMed1994

A structure-activity relationship study of benzylic modifications of 4-[1-(1-naphthyl)ethyl]-1H-imidazoles on alpha 1- and alpha 2-adrenergic receptors.

The naphthalene analog of medetomidine (1), 4-[1-(1-naphthyl)ethyl]-1H- imidazole (2), is a highly potent, selective alpha 2-adrenoceptor agonist. We have initiated a structure-activity relationship study of the replacement of the methyl group on the carbon bridge between the naphthalene and imidazole rings of 2 with a hydrogen, hydroxy, methoxy, carbonyl, or trifluoromethyl group and compared their biological activities with medetomidine 1 and the optical isomers of 2. Analogs of 2 were antagonists of alpha 2A-adrenoceptor-mediated human platelet aggregation and agonists on alpha 1- and alpha 2-adrenoceptors in guinea pig ileum. The rank order and potencies of these analogs on platelets (alpha 2A-subtype) and guinea pig ileum (alpha 1-subtype) were nearly the same, whereas racemic and S-(+)-2, desmethyl, and hydroxy analogs were potent agonists on alpha 2-adrenoceptors in guinea pig ileum. With the exception of the desmethyl analog 5, none of the other analogs were as potent as the parent drug 2 on alpha 2A- (human platelets), alpha 1- (guinea pig ileum), or alpha 2- (guinea pig ileum) adrenergic receptor systems. As with analog 2, the desmethyl- and methoxy-substituted analogs retained a greater alpha 2/alpha 1-selectivity in both functional (agonist activity) and biochemical (receptor displacement) studies. Receptor binding studies indicate that S-(+)-2 possessed greater affinity than the R-(-)-isomer on both alpha 1- and alpha 2-adrenoceptors in rat brain. In addition, R-(-)-2 did not show agonist activity in alpha 2-adrenoceptors of guinea pig ileum and was 10-fold more potent than S-(+)-2 as an antagonist of alpha 2A-adrenoceptors in human platelets. Thus, the nature of the substituent and the chirality at the carbon bridge between the naphthalene and imidazole rings play an important role in maintaining potent alpha 2-adrenoceptor activity and high alpha 2/alpha 1-selectivity within the 4-substituted imidazole class.

Adrenergic alpha-Agonists↗
PubMed1994

Synthesis and biological activities of a new set of irreversibly acting 2-(4'-isothiocyanatobenzyl)imidazoline analogs in rat thoracic aorta.

IBI [2-(4'-isothiocyanatobenzyl)imidazoline, 3] has been shown to cause slow-onset, long-lasting contractions of rat thoracic aorta through a non-alpha-adrenergic receptor (non-alpha-AR) mediated mechanism. A series of IBI-related anlogs 7-14 and 16 was prepared to determine the structural requirements for the interaction with non-alpha-AR in rat aortic strips. All IBI analogs produced concentration-dependent contractile responses on rat thoracic aorta. Whereas the actions of analogs 7, 14, and 16 were partly mediated by alpha-ARs, the stimulatory activities of the remaining IBI analogs were unaffected by phenoxybenzamine pretreatment, suggesting that a non-alpha-adrenergic mechanism is involved. We have shown that the contractile actions of IBI and analogs 10-13 were not blocked with the imidazoline/guanidinium receptive site (IGRS) ligands idazoxan, cirazoline, or clonidine. However, the calcium channel blockers nifedipine or verapamil shifted the concentration-response curve of IBI and its analogs 10-13 to the right and reduced the maximal contractile responses. The action of IBI on rat thoracic aorta was reduced by the omission of extracellular calcium in the medium. These results suggest that the stimulatory activities of IBI and analogs 10-13 are not related to the activation of alpha-AR or IGRS receptors and are likely coupled to the voltage-dependent Ca2+ channels.

Animals↗
PubMed1994

Isomeric-activity ratios of trimetoquinol enantiomers on beta-adrenergic receptor subtypes: functional and biochemical studies.

Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline , TMQ] exists as two enantiomers, and the (-)-(S)-isomer is a potent beta-adrenergic receptor (beta-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)-and (R)-enantiomers of TMQ for interaction with beta-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer > > (R)-isomer] for stimulation of beta 1- and beta 2-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were stereoselective for the (-)-(S)-isomer in membranes of guinea pig left ventricle (beta 1) and lung (beta 2) giving IARs of 115 and 389, respectively; and in E. coli expressing human beta 1- and beta 2-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta 2-AR and rat beta 3-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each beta-AR subtype, that the isomers generally fail to differentiate between the beta-AR subtypes, and that, based upon differences in IAR within beta 3-AR containing systems, subtypes of atypical beta (or beta 3)-AR may exist in adipose tissue and smooth muscle.

Adrenergic beta-Agonists↗
PubMed1994

Biochemical and pharmacological characterization of high-affinity trimetoquinol analogs on guinea pig and human beta adrenergic receptor subtypes: evidence for partial agonism.

Radioligand binding assays were used to characterize the interaction of a series of trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoqui nol ine; TMQ] analogs with beta adrenergic receptors (beta-AR). The results indicated that TMQ analogs bound with similar affinities to guinea pig (heart, lung and skeletal muscle) and human (beta-AR in Escherichia coli) beta-1- and beta-2-AR subtypes. However, the isomers of TMQ and 8-fluoro-TMQ bound stereoselectively to beta-AR with the S-isomers having affinities at least 112- and 8-fold greater, respectively, than their corresponding R-isomers. In general, a direct relationship existed between TMQ analog binding to guinea pig beta-AR and functional activity on guinea pig right atria (beta-1) and trachea (beta-2). For selected halogenated TMQ analogs (3',5'-diiodo-TMQ, 3'-iodo-TMQ, 5,8-difluoro-TMQ and 5-iodo-TMQ) which had higher beta-AR affinities than TMQ, but were less potent beta-AR agonists than TMQ, this relationship was not seen. To explain this, the function of the TMQ analogs was analyzed at the level of the beta-AR-associated effector mechanism (i.e., G-protein and adenylyl cyclase). In Chinese hamster ovary cells expressing human beta-2-AR, TMQ and halogenated analogs bound to the receptor with high affinity (nanomolar range); however, they failed to effectively couple with beta-AR-associated G-protein and only partially activated receptor-associated adenylyl cyclase. Receptor occupancies of 0.14, 2 and 23% were required for (-)-isoproterenol, S-(-)-TMQ and 3'5'-diiodo-TMQ to produce equivalent cyclic AMP accumulations in human beta-2-AR Chinese hamster ovary cells. Thus, TMQ and halogenated TMQ derivatives bind stereoselectively to beta-AR with high affinity, and may be classified as partial beta-AR agonists.

Adrenergic beta-Agonists↗
PubMed1993

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

Inhibition of low density lipoprotein oxidation by thyronines and probucol.

Oxidation of low density lipoproteins (LDL) results in increased macrophage uptake of LDL which may contribute to the formation of macrophage-derived foam cells in the early atherosclerotic lesion. In this study we show that thyroxine (T4), its optical antipodes, certain desiodo analogs and probucol inhibited cupric sulfate-catalyzed oxidation of human LDL in a concentration-dependent manner as assessed by measuring the electrophoretic mobility, thiobarbituric acid reactive substances (TBARS) and LDL degradation in mouse macrophages. In Cu(2+)-catalyzed LDL oxidation at 24 hr, the TBARS level was 80 nmol/mg LDL protein/24-hr incubation. The concentrations (microM) of each agent producing 50% inhibition in the formation of oxidized LDL (IC50) for TBARS, electrophoretic mobility and macrophage degradation, respectively, were 1.13, 1.27 and 1.30 for reversed triiodothyronine; 1.33, 1.80 and 1.27 for triiodothyronine; 1.33, 1.37 and 1.37 for racemic thyroxine, DL-T4; 1.10, 1.40 and 1.50 for L-T4; 1.13, 1.33 and 1.23 for D-T4; and 1.47, 1.63 and 1.37 for probucol. No differences in inhibitory potency were observed when rT3, T3, the optical antipodes of T4 and the hydrophobic antioxidant drug probucol were compared. In air-induced LDL oxidation, TBARS was 16.1 nmol/mg LDL protein/6-hr incubation. The IC50 concentrations (microM) for TBARS and diene conjugation, respectively, were 0.187 and 0.336 for D-T4; 0.205 and 0.243 for L-T4 and 1.30 and 3.02 for probucol. With air-induced LDL oxidation conditions, the L-T4 concentrations included the physiological range, and thyroid-binding globulin did not modify the inhibitory effect of the endogenous enantiomer, L-T4. Putative uptake of this stereoisomer into LDL inhibited oxidation of these lipoproteins. Since concentrations of these thyronines which blocked air-induced LDL oxidation were in the physiological range, we conclude that thyronines, like the pharmacological agent probucol, limit the oxidative modification of LDL and thus may serve as natural inhibitors of atherogenesis.

Air↗
PubMed1993

Interactions of nonprostanoid trimetoquinol analogs with thromboxane A2/prostaglandin H2 receptors in human platelets, rat vascular endothelial cells and rat vascular smooth muscle cells.

Trimetoquinol (TMQ), a nonprostanoid compound, inhibits thromboxane A2 agonist-induced responses in platelets and vascular smooth muscle. Sixteen TMQ analogs were used to examine the stereochemical requirements of the interaction with thromboxane A2/prostaglandin H2 (TP) receptor sites in human platelets (HP), and cultured rat vascular endothelial (RVEC) and smooth muscle (RVSMC) cells. [3H]SQ 29548 was used as the ligand for TP receptors. The receptor binding affinities of these TMQ analogs for TP receptors in HP, RVEC and RVSMC were highly correlated with each other, and to their reported inhibitory potency values against U46619-induced HP aggregation and serotonin secretion, and contraction of rat aorta. TP receptor binding affinities of TMQ and 8-fluoro TMQ isomers were highly stereoselective (R-isomer > S-isomer), and only the 8-fluoro TMQ isomers gave qualitatively different functional responses in rat aorta. The affinity of TMQ for TP receptors was increased by addition of iodine and fluorine atoms at the 5- and 8-positions of the catechol ring or by replacement of the methoxy groups with iodine atoms on the 1-benzyl ring system. The results indicate that: 1) the stereochemical requirements of TMQ analogs for interaction with TP receptors in these cell systems are the same; 2) although TMQ analogs act as TP receptor antagonists, differences in functional responses by 8-fluoro TMQ isomers in platelets and aorta are not explained by their relative binding affinities to TP receptors; and 3) asymmetric halogenated TMQ analogs should be useful as affinity probes for further characterization of TP receptors.

Adrenergic beta-Agonists↗
PubMed1992

Synthesis and alpha-adrenergic activities of 2- and 4-substituted imidazoline and imidazole analogues.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

Adrenergic alpha-Agonists↗
PubMed1992

Synthesis of halogenated trimetoquinol derivatives and evaluation of their beta-agonist and thromboxane A2 (TXA2) antagonist activities.

The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate beta 1 (guinea pig atria) and beta 2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both beta-adrenergic systems and gave a rank order of stimulatory potency of 1 much greater than 6 greater than or equal to 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 greater than 6 much greater than 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On beta-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5-position of TMQ completely abolished both beta 1- and beta 2-adrenergic agonist activities while imparting weak antagonist activity on beta 1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8-(trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on beta-adrenergic systems and TXA2 systems. On beta-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)-8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.

Adrenergic beta-Agonists↗
PubMed1992

Effects of the stereochemical orientation of phenethylamines and imidazolines on alpha-adrenergic receptor-mediated DNA synthesis in primary cultured rat hepatocytes.

The hepatic alpha 1-adrenergic receptor mediates a variety of hepatic functions including respiration, glycogenolysis, gluconeogenesis, and growth. We have utilized a rat primary hepatocyte culture system to show that the alpha 1-adrenergic receptor can be activated in a stereoselective manner by a series of phenethylamines and catecholimidazolines resulting in the stimulation of DNA synthesis as determined by [3H]thymidine incorporation. The phenethylamines adhered to the Easson-Stedman hypothesis with a rank order of potency of (-)-(R)-norepinephrine (NE) greater than (+)-(S)-NE greater than the desoxy analog dopamine (DA) for the stimulation of DNA synthesis. However, the 2-substituted catecholimidazolines did not follow this trend and demonstrated an order of potency of the desoxy analog 3,4-dihydroxybenzyl imidazoline (DHT) greater than or equal to (-)-(R)-2-(3,4,alpha-trihydroxybenzyl)imidazoline (TBI) greater than (+)-(S)-TBI. 4-Substituted catecholimidazolines were less potent as inducers of DNA synthesis than the corresponding 2-substituted analogs with an order of potency of (+)-(R)-4-(3,4-dihydroxybenzyl)imidazoline (DBI) greater than (+,-)-(R,S)-DBI greater than (-)-(S)-DBI. When the beta-hydroxyl moiety of NE is replaced with an amino group as in 3,4-dihydroxyphenylethylenediamine, the isomers are less active than the beta-hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic alpha 1-adrenergic receptor can recognize various isomeric forms of these compounds and that hepatocellular growth can be modulated in a stereoselective manner by phenethylamines and imidazolines.

Animals↗
PubMed1992

Resolution and adrenergic activities of the optical isomers of 4-[1-(1-naphthyl)ethyl]-1H-imidazole.

Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.

Adrenergic alpha-Agonists↗
PubMed1991

Diversity of the pharmacological actions of some tolazoline analogues in human platelets and rat aorta.

Tolazoline and two 4'-substituted benzyl analogues, 2-(4'-aminobenzyl) imidazoline (ABI) and 2-(4'-isothiocyanatobenzyl)imidazoline (IBI) were synthesized and evaluated for adrenoceptor activity in human platelets (alpha 2) and rat aorta (alpha 1), respectively. IBI was prepared as an affinity label for alpha-adrenoceptors and compared with chloroethylclonidine. Tolazoline, IBI, ABI and chloroethylclonidine inhibited the primary and secondary waves of epinephrine-induced human platelet aggregation. In aspirin treated platelets, primary wave aggregatory responses to epinephrine were blocked in a competitive manner by tolazoline, ABI. IBI and chloroethylclonidine giving pA2 values of 6.33, 6.12, 4.71 and 5.70, respectively. Only IBI blocked the aggregation responses to ADP (secondary wave only) arachidonic acid and U46619 (a thromboxane A2 agonist). Arachidonic acid-induced serotonin release and malondialdehyde formation and thrombin-induced release of [3H]arachidonic acid from membrane phospholipids were also blocked by IBI. These data indicate that IBI blocks arachidonic acid release, prostaglandin biosynthesis and the action of thromboxane A2. One hour exposure of aspirin treated platelets with IBI abolished inhibitory effects against epinephrine induced aggregation. In contrast to human platelets, both ABI and IBI produced contractions of rat aorta; however, only the responses to ABI were blocked in a competitive manner by the alpha-antagonists, phentolamine, prazosin, and SKF 104078. Moreover, idazoxan blocked the stimulatory actions of IBI, cirazoline and phenylephrine on rat aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1991

Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo.

Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗