Synthesis and antiarrhythmic activity of novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega- hydroxyalkyl]-1H-imidazolium salts and related compounds. 2

Novel analogues of the class III antiarrhythmic agent 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, 1 (CK-1649), were prepared and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structure-activity relationships are discussed for a series of 11 compounds. One compound, N-[4-[1-hydroxy-2-(4,5-dihydro-2-methyl-1H-imidazol-1- yl)ethyl]phenyl]methanesulfonamide hydrochloride, 9, was comparable in activity to 1 in vitro and prolonged the functional refractory period in anesthetized dogs when given intraduodenally. Unlike 1, compound 9 was ineffective at preventing ventricular tachycardia induced by programmed electrical stimulation in anesthetized dogs 24 h after an acute myocardial infarction.     

Autoradiographic localization of beta-adrenoceptors in pig lung using [125I]-iodocyanopindolol.

The binding of the beta-adrenoceptor radioligand [125I]-iodocyanopindolol (I-CYP) has been studied in pig lung parenchyma and the distribution of binding sites visualised by light microscopic autoradiography. I-CYP binding was saturable (maximum binding capacity Bmax = 51 +/- 3 fmol mg-1 protein), involving sites with high affinity (dissociation constant KD = 73 +/- 10 pM). Specific I-CYP binding was displaceable both by beta-adrenoceptor agonists ((-)-isoprenaline greater than (-)-adrenaline greater than (+/-)-fenoterol greater than (-)-noradrenaline greater than (+)-isoprenaline greater than (+/-)-RO363) and antagonists ((+/-)-propranolol greater than ICI-118551 greater than atenolol), indicating a predominance of beta 2-adrenoceptors. Further analysis showed that displacement data for the beta 1-selective antagonist atenolol and the beta 2-selective antagonist ICI-118551 were fitted best to a 2 binding site model and that both beta 1- and beta 2-adrenoceptors were present in pig lung in the ratio 28:72 respectively. Autoradiographic grains were localized over tissue and were most dense over alveolar walls greater than vascular endothelium greater than vascular smooth muscle greater than bronchial smooth muscle = bronchial epithelium. Atenolol (10(-5) M) caused a 31% reduction in specific grain density over alveolar wall tissue, while a 10 fold lower concentration of ICI-118551 (10(-6) M) caused a 50% decrease. These results are consistent with binding data in pig lung parenchyma demonstrating a mixed population of beta-adrenoceptors with a predominance of the beta 2 subtype.(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium channels in normal and dystrophic hamster cardiac muscle. [3H]nitrendipine binding studies

Progressive cardiac cell necrosis in the dystrophic hamster may be related to intracellular calcium overload, particularly as necrosis is prevented by treatment with calcium channel antagonists. Calcium overload could arise as a consequence of an imbalance in calcium influx, efflux and/or sequestration. The possibility that increased numbers of calcium channels in myopathic cells leads to excessive calcium influx has been studied by assaying the number of [3H]nitrendipine [( 3H]NTP) binding sites in cardiac muscle preparations. Crude homogenate and partially-purified ventricular muscle preparations from 60-day-old normal and genetically dystrophic hamsters were compared in this study. The results of equilibrium binding studies showed that, in both crude and partially-purified membrane preparations, the affinity and the maximum number of [3H]NTP binding sites in normal muscle were not significantly different from those measured in dystrophic muscle. For the homogenate preparation, the KD values were 0.07 +/- 0.01 and 0.08 +/- 0.01 nM for normal and dystrophic tissues, respectively, and the Bmax values were 62 +/- 6 and 73 +/- 6 fmol/mg protein for normal and dystrophic preparations respectively. These data show that a simple increase in the number of [3H]NTP binding sites is unlikely to account for calcium overload in the cardiomyopathic hamster.     

Actions of the novel thromboxane A2 receptor antagonist sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)-ethylidene]-6,11- dihydrodibenz[b,e]oxepine-1-carboxylate monohydrate on smooth muscle preparations.

The effects of KW-3635 (sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)- ethylidene]-6,11-dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) on smooth muscle preparations were examined. In isolated guinea-pig aorta, KW-3635 competitively inhibited the U-46619 (a thromboxane mimetic) induced contractions (pA2 = 7.74), the effect being more potent than those of sulotroban and daltroban. In canine saphenous vein, KW-3635 also antagonized the U-46619-induced contraction (pA2 = 8.11). In this preparation, solutroban and daltroban, but not KW-3635, exhibited intrinsic agonistic action. KW-3635, even at a high concentration of 10(-5) mol/l did not affect the norepinephrine- or KCl-induced contractions of guinea-pig or rat aorta, prostaglandin (PG)E2- or PGF2 alpha-induced contractions of guinea-pig ileum nor the PGE2-induced contraction of rat fundus. KW-3635 at concentrations higher than its thromboxane A2- (TxA2-)antagonistic one, non-competitively inhibited the PGF2 alpha-induced contractions of guinea-pig aorta (pD2' = 6.23), as was the case with daltroban. The inhibitory effect of KW-3635 (3 x 10(-6) mol/l) on U-46619-induced contractions of guinea-pig aorta persisted for longer than 2 h following washout of the tissue, whereas that of daltroban (10(-5) mol/l completely disappeared at 1 h after the washout. In anesthetized guinea-pigs, KW-3635 at doses of 10 to 1000 micrograms/kg (i.v.) inhibited U-46619 (1 microgram/kg i.v.)-induced pressor responses in a dose-dependent manner. The effect of KW-3635 (0.1 to 1 mg/kg i.v.) persisted for longer than 3 h. These results demonstrate that KW-3635 is a potent and specific TxA2 antagonist without agonistic action in vascular smooth muscles. KW-3635 is considered to be a promising candidate for the treatment of patients with disorders mediated via TxA2.     

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.     

Synthesis and muscarinic receptor activity of ester derivatives of 2-substituted 2-azabicyclo[2.2.1]heptan-5-ol and -6-ol.

Radioligand binding affinities of four new muscarinic antagonists and six potential muscarinic agonists which possess the 2-alkyl-2-azabicyclo[2.2.1]heptane ring system have been determined in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations to examine the selectivity for subtypes of muscarinic receptor. The efficacies of the potential muscarinic agonists were determined by the ratio of binding affinities against [3H]QNB and [3H]Oxo-M. Four muscarinic antagonists which have the 2,2-diphenylpropionate side chain at either the C5 (5-endo or 5-exo) or the C6 (6-endo or 6-exo) positions did not discriminate between the subtypes of muscarinic receptors. The 2,2-diphenylpropionate 5-endo substituted compound was the most potent, showing affinities between 4.23 x 10(-10) and 1.18 x 10(-9) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. The rank order of ester potency was 5-endo greater than 5-exo greater than 6-endo greater than 6-exo. A molecular modeling study based on the pharmacophore developed for azaprophen was used to account for the relative potency of these antagonists. Six potential muscarinic agonists which have acetoxy groups in the C5 or C6 position with an N-methyl or N-benzyl substituent did not discriminate subtypes of muscarinic receptors and had affinities between 6.63 x 10(-6) and 4.76 x 10(-5) M in rat heart, rat brain, and m1- or m3-transfected CHO cell membrane preparations. exo-2-Methyl-5-acetoxy-2-azabicyclo[2.2.1]heptane was the most efficacious partial agonist.     

Synthesis and biological evaluation of 9-[5'-(2-oxo-1,3,2-oxazaphosphorinan-2-yl)-beta-D-arabinosyl]ade nine and 9-[5'-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-beta-D-arabinosyl]ade nine: potential neutral precursors of 9-[beta-D-arabinofuranosyl]adenine 5'-monophosphate

9-[5'-(2-Oxo-1,3,2-oxazaphosphorinan-2-yl)-beta-D-arabinosyl]adeni ne (1c) and 9-[5'-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-beta-D-arabinosyl]adeni ne (1d) were synthesized by reaction of 9-[beta-D-arabinofuranosyl]adenine with phosphoryl chloride with 1-amino-3-propanol and 1,3-propanediol, respectively. 1c consisted of a mixture of diastereomers, while 1d was enantiomerically homogeneous. The structures of these compounds were established by spectral (1H NMR, MS, UV) and elemental analyses. Both 1c and 1d were resistant to degradation by 5'-nucleotidase, alkaline phosphatase, venom phosphodiesterase, crude snake venom, adenosine deaminase, and adenylate deaminase. Neither compound was significantly biotransformed by mouse hepatic microsomal preparations in the presence of an NADPH-generating system. Compound 1c was marginally effective at prolonging the life span of mice bearing P-388 leukemia; compound 1d, however, was inactive.     

Intestinal transfer of sodium [14C]taurocholate in streptozotocin-treated rats

The effect of streptozotocin (SZ) administration on sodium [14C]taurocholate (TC) transmural transfer was studied in the everted rat ileum. The excretion of fecal bile acids was also studied in living rats injected with that compound. The viability of the preparation used for the in vitro experiments was evaluated by light microscopy and by the rate of glucose uptake by tissue from the mucosal fluid. The results obtained showed that TC transfer to the serosal fluid was impaired after 24 h of SZ injection, as well as the active transport observed in control preparations. The amount of TC accumulated in the intestinal tissue was also diminished. In addition, total ATPase activity of tissue was decreased, and intracellular electrolyte concentration was altered. Therefore, a slower saturation of binding sites could be responsible for the effects of SZ on TC tissue accumulation, and a decreased ATPase activity for the impairment of the TC concentrative transport system. The results observed in vitro were supported by data in vivo because fecal bile acid excretion was significantly diminished in SZ-treated rats.     

The binding of 1,3-[3H]-dipropyl-8-cyclopentylxanthine to adenosine A1 receptors in rat smooth muscle preparations.

1. The binding of 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]-DPCPX), an antagonist radioligand selective for adenosine A1 receptors, was studied in rat duodenum, colon muscularis mucosae and longitudinal muscle, urinary bladder and vasa deferentia. 2. [3H]-DPCPX bound with high affinity to a single site in all membrane preparations studied with the exception of the rat urinary bladder in which no specific binding was detected. The affinity (Kd) of the binding site for [3H]-DPCPX was similar in all membrane preparations, the colon longitudinal muscle (1.18 +/- 0.47 nM), colon muscularis mucosae (0.84 +/- 0.15 nM), duodenum (1.59 +/- 0.18 nM) and vasa deferentia (0.93 +/- 0.17 nM). The density of [3H]-DPCPX binding sites was similar in the duodenum (38.8 +/- 4 fmol mg-1 protein), muscularis mucosae (43 +/- 3.5 fmol mg-1 protein) and vasa deferentia (43.3 +/- 12.2 fmol mg-1 protein), but in the longitudinal muscle 6-7 fold more binding sites (295 +/- 70 fmol mg-1 protein) were identified. 3. Inhibition studies using DPCPX (0.1-100 nM), N6-cyclopentyladenosine (CPA) (0.1-100 nM), 5'-N-ethylcarboxamidoadenosine (NECA) (2 nM-10 microM) and (R)-N6-phenylisopropyladenosine (R-PIA) (1 nM-1 microM) to displace the binding of [3H]-DPCPX at a concentration around the Kd value (1 nM), demonstrated an order of potency of displacement in all tissues of DPCPX > or = CPA > R-PIA > NECA. This potency order is characteristic of an A1 receptor, indicating that [3H]-DPCPX binds to adenosine A1 receptors in the rat duodenum, colon and vasa deferentia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Contractile effects of cysteamine on the guinea-pig ileum

Cysteamine (beta-mercaptoethylamine HCl) (1.0-40.0 mM) induced a concentration-dependent increase in tonic and phasic contractions of segments of guinea-pig ileum in vitro. Myenteric plexus-longitudinal muscle (MPLM) preparations also responded with an increase in tonic contractions but phasic contractions were either greatly reduced or absent, indicating that these were a response of the circular muscle. Atropine (5 microM) inhibited the cysteamine-induced contractions, whereas hexamethonium and guanethidine had no effect, suggesting that cysteamine was acting at least partly via a cholinergic mechanism involving muscarinic receptors. Tetrodotoxin increased the phasic contractions of ileal segments, but had no effect on the tonic component. Treatment of MPLM preparations with morphine (1 microM) resulted in a small reduction in responsiveness to cysteamine, and blocked electrically-induced contractions by at least 90%. Since morphine acts by inhibiting acetylcholine release via hyperpolarization of intrinsic neurones, a small but significant part of the cysteamine-induced contractions probably resulted from stimulation of acetylcholine release from intrinsic neurones. Following a response to high cysteamine concentrations (greater than 15 mM) tissues were refractory to subsequent cysteamine administration. Cross-desensitization between cysteamine and acetylcholine also occurred, as short-term (1-3 min) incubation of MPLM preparations with high concentrations of either compound (1-10 microM acetylcholine or 20 mM cysteamine) resulted in a reduced responsiveness to both. A reduced sensitivity to acetylcholine or cysteamine was obtained following long-term (45 min) incubation with acetylcholine (1 microM). Removal of Na+ from the incubation medium negated this effect. In contrast, the refractoriness to acetylcholine or cysteamine following long-term (45 min) incubation with cysteamine (20 mM) was accentuated in low Na+ medium. It is suggested that cysteamine induces a contraction of both the circular and longitudinal muscle of the guinea-pig ileum by stimulating the release of acetylcholine from intrinsic neurones, by an action at the level of the smooth muscle muscarinic receptor, and possibly by a non-cholinergic mechanism. However, the mechanisms by which acetylcholine and cysteamine induce tissue refractoriness probably differ.     

Antiallergic 9-oxo-11-hydroxy-5H,9H-[2]benzopyrano[4,3-g][1]benzopyrans

The synthesis and properties of the title compounds 1 are described. Several of these compounds, in addition to being potent inhibitors of the passive cutaneous anaphylaxis reaction of rats against egg albumin challenge, significantly block the effects of several mediators of anaphylaxis in isolated smooth muscle preparations. An improved procedure for the isolation and partial purification of SRS-A from chopped guinea pig lung tissue is also described.     

Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Qic8]bradykinin).

HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a new B2 antagonist, was compared to R-493 (D-Arg[Hyp3-D-Phe7,Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36-9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykinin, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive even at low concentrations (7.7 x 10(-9) M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.     

2-Oxo-2H-Pyrimido[2,1-b]benzothiazoles inhibit brain benzodiazepine receptor binding in vitro

2-Oxo-2H-pyrimido[2,1-b]benzothiazole derivatives were found to inhibit the in vitro binding of (3)H-Ro 15-1788 ((3)H-flumazenil) to rat cortical benzodiazepine receptors with IC(50) values in the range of 0.7-13 micromol/l. The most potent compound, 2-oxo-4-phenyl-2H-pyrimido[2,1-b]- benzothiazole showed a similar potency to inhibit (3)H-Ro 15-1788 binding to membrane preparations of rat brain cortex, cerebellum and hippocampus as well as to various subunit combinations of recombinant human gamma-aminobutyric acid(A)/benzodiazepine receptors. Scatchard plot analysis showed that 2-oxo-4-phenyl-2H-pyrimido[2,1-b]benzothiazole is a competitive inhibitor of (3)H-Ro 15-1788 binding to rat brain cortical membrane preparations.     

Depletion kinetics of 14C-sulfamethazine [4-amino-N-(4, 6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] metabolism in swine

Swine weighing 60-70 kg were orally administered 14C-sulfamethazine [4-amino-N-(4,6-dimethyl-2-pyrimidinyl)benzene[U-14C]sulfonamide] at 12-hr intervals for 7 days (165 mg/dose; 0.126-5.04 mCi/mmol). The animals were sacrificed at 8 hr or 2, 5, or 10 days after the last dose was given and tissues were assayed for total 14C activity. The presence of 14C-labeled sulfamethazine, N4-acetylsulfamethazine, desaminosulfamethazine, and the N4-glucose conjugate of sulfamethazine in blood, liver, kidney, skeletal muscle, and adipose tissue was verified by HPLC and GC-MS analysis. Total 14C residue levels in all tissues examined had dropped to less than 0.1 ppm sulfamethazine equivalents by day 10 of the depletion period. The mean half-life (t1/2) for sulfamethazine, the N4-glucose conjugate of sulfamethazine, and N4-acetylsulfamethazine was estimated to be 0.8 day. In some tissues, the depletion of the N4-glucose conjugate of sulfamethazine and N4-acetylsulfamethazine had decreased significantly between days 5 and 10, resulting in an approximate doubling of the t1/2 for that period. In contrast, the half-life of desaminosulfamethazine varied from a mean of 0.96 day during the 8-hr-5-day depletion period to 3.7-9.1 days during the 5- 10-day depletion period. In most tissues, the t1/2 for the 14C-activity in the methanol-insoluble fraction increased by 3-5-fold between days 5 and 10 of the depletion period. No predictable relationship was observed between blood sulfamethazine or metabolite levels and total residue levels in the tissues.     

Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 1. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetates.

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 10. Potency was generally markedly reduced by placing substituents on the phenyl ring of the phenoxypropanolamine unit of 8; only the 2-fluoro analogue 16 had comparable potency to 8. Other structure-activity relationships are discussed. Further testing of 8 (ICI 198157) has shown that in the rat it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1 and beta 2 adrenergic receptors in other tissues. It increases metabolic rate, as judged by an increase in oxygen consumption, and in the genetically obese Zucker rat it causes a reduced rate of weight gain. This class of compound may be useful in the treatment of obesity in man.     

Pharmacological characterization of a substance P antagonist, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P.

The substance P antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]-substance P produced parallel log dose-response curve shifts to both substance P and eledoisin on five in vitro smooth muscle preparations. The slope values of Arunlakshana-Schild plots were not significantly different from unity suggesting that it acts as a simple competitive antagonist on all five preparations with an association constant (Ka) in the range of 0.3-1.5 X 10(6)M-1. The Ka value of the antagonist was always slightly greater when tested against eledoisin than against substance P; however, this difference appears too small to suggest that these two agonists are acting on different receptor sub-types.     

Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in the guinea-pig ileum myenteric plexus.

The cross-tolerance and convergent dependence between morphine and the cannabimimetic agent R(+)-[2,3-dihydro-5-methyl-3[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-+ ++benzoxazin-yl]-(1-naphthalenyl) methanone mesylate (WIN 55,212-2) were assessed in vitro on guinea-pig ileum. To induce tolerance and dependence the myenteric plexus-longitudinal muscle was incubated at 37 degrees C for 5 h with a fixed concentration representing the IC50 for each compound. Myenteric plexus-longitudinal muscle exposed to WIN 55,212-2 (5 x 10(-8) M) was less sensitive to its inhibitory effect on electrically evoked contractions than naive myenteric plexus-longitudinal muscle. The exposure to cannabinoid induced a parallel rightward shift in the lower part of the concentration-response curve of WIN 55,212-2 and a marked reduction in the maximal inhibitory effect of the drug. Myenteric plexus-longitudinal muscle tolerant to WIN 55,212-2 was subsensitive to the inhibitory effect of morphine on the twitch response. The cross-tolerance between WIN 55,212-2 and morphine was bidirectional. In fact, after 5 h the morphine (10(-7) M)-incubated myenteric plexus-longitudinal muscle was less sensitive to the inhibitory effect of WIN 55,212-2. The tissue tolerant to morphine or WIN 55,212-2 was tested for the presence of physical dependence. Naloxone (10(-5) M) produced a typical withdrawal contracture in morphine-tolerant myenteric plexus-longitudinal muscle which could be reduced by a 15-min pretreatment with WIN 55,212-2 (5 X 10(-8) M). In contrast, SR141716 (10(-6) M) [N-(piperidino)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyr azole-carboxamide], a concentration which fully antagonized the inhibitory effect of WIN 55,212-2 (10(-7) M) in control preparations, did not produce significant contracture in WIN 55,212-2-tolerant myenteric plexus-longitudinal muscle. The mechanisms underlying the cross-tolerance and convergent dependence remain to be ascertained.     

Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies

There is an ongoing discussion on whether or not high beta(1)-adrenoceptor selectivity of beta-adrenoceptor antagonists may be favorable in the treatment of patients with heart failure. The present study compared the beta(1)-adrenoceptor selectivity of nebivolol and bisoprolol with that of carvedilol in the human myocardium, using a binding assay in conjunction with either the hydrophilic ligand (+/-)-[3H]4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on HCl ([3H]CGP 12.177) or the lipophilic ligand [125I]iodocyanopindolol as radiolabeled compound. Measurements were made using membrane preparations obtained from identical nonfailing donor hearts. beta-adrenoceptor density was found to be slightly higher when [125I]iodocyanopindolol was used compared to [3H]CGP 12.177 (256+/-15 and 213+/-18 fmol/mg protein, respectively). When the highly beta(1)-adrenoceptor-selective compound 2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4-trifluoromethyl)-1-H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide (CGP 20.712A) and the highly beta(2)-adrenoceptor-selective compound erythro-(+/-)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-ol HCl (ICI 118.551) were used in competition experiments, a similar proportion of beta(1)-adrenoceptors was seen for [3H]CGP 12.177 (69.3+/-1.6%) and for [125I]iodocyanopindolol (67.0+/-2.1%). K(i)(beta(1)) and K(i)(beta(2)) were obtained in the presence of 50 nM ICI 118.551 and 300 nM CGP 20.712A. The rank order of beta(1)-adrenoceptor selectivity (K(i)(beta(2))/K(i)(beta(1)) ratio) was nebivolol (for [3H]CGP 12.177 46.1 and for [125I]iodocyanopindolol 22.5)>bisoprolol (13.1 and 6.4)>carvedilol (0.65 and 0.41). To investigate whether in vivo metabolized nebivolol retains high beta(1)-adrenoceptor selectivity, serum specimens were collected before and 2 h after oral administration of 5 mg nebivolol. The samples were used for [125I]iodocyanopindolol binding studies with the myocardial membrane preparations. In these samples, the binding of [125I]iodocyanopindolol to beta(1)-adrenoceptors was inhibited by 46.4+/-5.3%, whereas the binding to beta(2)-adrenoceptors was inhibited by 20.5+/-1.1% compared to that of control samples. It is concluded that nebivolol is approximately 3.5 times more beta(1)-adrenoceptor-selective than bisoprolol in the human myocardium. Furthermore, in vivo metabolized nebivolol retains beta(1)-adrenoceptor selectivity.     

Neuroleptic activity of 10-(4-methyl-1-piperazinyl)-thieno[3,2-b] [1,5]benzoxazepine and benzothiazepine derivatives.

Two series of compounds, structurally related to clozapine (CAS 5786-21-0), were tested for their neuroleptic activity. The derivatives 7-chloro-10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzoxazepine and 7-chloro-10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzothiazepine at high doses were not cataleptogenic and only very weakly antagonized the amphetamine-or apomorphine-induced stereotyped behaviour in the rat, whereas at low doses they antagonized the amphetamine-induced hypermotility in mice. Thus these compounds might be efficient neuroleptics with little propensity to cause extrapyramidal side effects. On the other hand, the unsubstituted compound 10-(4-methyl-1-piperazinyl)-thieno[3,2-b][1,5]benzothiazepine appeared to be an efficient neuroleptic agent with a greater propensity to cause these side effects.