In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist mizolastine with H1 receptors in the rodent.

The interaction of mizolastine (CAS 108612-45-9, SL 85.0324) with histamine H1 receptors has been evaluated in the rodent. Mizolastine inhibited with high affinity (IC50 = 47 nmol/l) the binding of [3H]pyrilamine to histamine H1 receptors in guinea pig cerebellar membranes and sections. The order of potency of mizolastine and various H1 antagonists in this binding assay was the following: cyproheptadine > pyrilamine > mequitazine > mizolastine > astemizole > terfenadine > cetirizine > loratadine. Mizolastine also potently antagonized the contractile effects of histamine in the guinea pig ileum (pA2 = 8.5) and histamine-induced stimulation of phosphoinositide turnover in rat cortical slices (IC50 = 0.35 mumol/l). In contrast, this compound displayed very low affinity for serotonergic, noradrenergic and muscarinic cholinergic receptors as evidenced in both binding assays and functional tests. In guinea pig cerebellar membranes, [3H]mizolastine labelled in a saturable and reversible manner a single population of binding sites with Kd and Bmax values of 1.1 nmol/l and 635 fmol/mg protein, respectively. [3H]Mizolastine binding in guinea pig cerebellar membranes was inhibited by histamine (IC50 = 30 mumol/l) and by drugs that possess affinity for the H1 receptor such as pyrilamine (IC50 = 1 nmol/1), DL-chlorphenyramine (IC50 = 6.4 nmol/l) terfenadine (IC50 = 6 nmol/l) and loratadine (IC50 = 50 nmol/l). At concentrations lower than 10 mumol/l, the H2 receptor ligands dimaprit and cimetidine and the H3 receptor ligands burimamide and 4-methyl-histamine failed to displace [3H]mizolastine binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfuzosin, a selective alpha 1-adrenoceptor antagonist in the lower urinary tract.

1. Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin. 2. The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated. [3H]-prazosin was potently displaced by alpha 1-adrenoceptor specific agents including alfuzosin, its (+)- and (-)-enantiomers and prazosin (IC50 0.035, 0.023, 0.019 and 0.004 microM, respectively), but only weakly by alpha 2-adrenoceptor selective agents, for example, yohimbine (IC50 = 6.0 microM). 3. In the pithed rat, alfuzosin (0.03-0.3 mg kg-1, i.v.) markedly inhibited pressor responses produced by the alpha 1-selective agonist, cirazoline but inhibited only slightly responses to the alpha 2-selective agonist, UK 14,304. Alfuzosin (1 mg kg-1, i.v.) had minimal effects against responses mediated by stimulation of prejunctional alpha 2-receptors (UK 14,304-induced inhibition of sympathetic tachycardia). 4. In the anaesthetized cat, alfuzosin (0.001-1 mg kg-1, i.v.) and prazosin (0.001-0.3 mg kg-1, i.v.) produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular alpha 1-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-1 alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure. 5. Alfuzosin is a potent selective alpha1-adrenoceptor antagonist in tissues of the lower urinary tract including the human prostate. This provides a pharmacological basis for its use in the treatment of benign prostatic hypertrophy.

Comparative analysis of beta-1 adrenoceptor agonist and antagonist potency and selectivity of cicloprolol, xamoterol and pindolol.

The partial beta adrenoceptor agonist properties of cicloprolol, xamoterol and pindolol have been compared in vivo (anesthetized catecholamine-depleted or pithed rats) and in vitro (guinea pig or rat right atria and guinea pig tracheal muscle preparations) conditions. All three compounds increased heart rate in the former preparations, and their intrinsic activities relative to isoproterenol were 0.7, 0.65 and 0.45, respectively. The positive chronotropic effects of cicloprolol or xamoterol were competitively antagonized by betaxolol or propranolol; however, part of those induced by pindolol were resistant to these beta adrenoceptor antagonists. None of these compounds increased the spontaneous beating rate of isolated guinea pig atria; however, xamoterol only increased heart rate in isolated rat atria, and its intrinsic activity with respect to isoproterenol was 0.4. Pindolol, xamoterol and cicloprolol behaved as competitive beta-1 adrenoceptor antagonists against isoproterenol-induced tachycardia in a pithed rat model. In order to mimic the intrinsic effects of the partial agonist drugs, control dose-response curves for isoproterenol were determined in pithed rats in which the base-line heart rate was elevated by thoracic spinal cord stimulation. In this in vivo preparation, xamoterol and pindolol were more potent beta-1 adrenoceptor antagonists than cicloprolol; however, cicloprolol and xamoterol, in contrast to pindolol, were selective for beta-1 adrenoceptors. In isolated spontaneously beating guinea pig right atria, cicloprolol and xamoterol were equipotent beta-1 adrenoceptor antagonists but were about 50 times less potent than pindolol. In isolated rat atria, the beta-1 adrenoceptor antagonist potency of xamoterol was greater (pA2 = 8.7) than in guinea pig atria (pA2 = 7.8). The potencies of cicloprolol and pindolol did not vary between these species. In catecholamine-depleted rats, high i.v. doses of cicloprolol had vasodilator activity that was partly mediated by beta-2 adrenoceptors. In carbachol-contracted guinea pig trachea, cicloprolol and xamoterol, in contrast to pindolol, were relatively inactive against isoproterenol-induced relaxation. In conclusion, cicloprolol and xamoterol, similarly to pindolol, behave as agonists and antagonists of beta-1 adrenoceptors. However, only cicloprolol and xamoterol show an elevated degree of selectivity toward the beta-1 adrenoceptor subtype.

Synthesis of a series of compounds related to betaxolol, a new beta 1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases.

A series of para-substituted phenoxypropanolamines has been synthesized and tested for beta-adrenoceptor blocking activity. Some derivatives (8, 11, 12, 20, 21) exhibited greater in vitro potency than the reference drugs metoprolol and propranolol. This series, in contrast to propranolol but similar to metoprolol, possesses cardioselectivity. The 3-[p-[(cycloalkylmethoxy)ethyl]phenoxy]-1-substituted-amino-2-prop anol derivatives 8 (cyclopropylmethoxyethyl: betaxolol) and 11 (cyclobutylmethoxyethyl) produced antihypertensive effects in spontaneously hypertensive rats. Betaxolol (Kerlon, 8) was found to exhibit an appropriate preclinical pharmacological and human pharmacokinetic profile (elevated oral bioavailability and prolonged plasma half-life) for the treatment of chronic cardiovascular diseases such as hypertension and angina.

Synthesis and antihypertensive activity of a series of 4-amino-6,7-dimethoxyquinazoline derivatives.

A series of N2-[(acylamino)alkyl]-6,7-dimethoxy-2,4-quinazolinediamines was synthesized as potential alpha 1-adrenoceptor antagonists. When administered to spontaneously hypertensive rats at 10 mg/kg po, a number of propanediamine derivatives showed good antihypertensive activity, whereas the ethanediamine derivatives, albeit being structurally more closely related to prazosin, were devoid of this property. The most active derivative, N-[3-[(4-amino-6, 7-dimethoxy-2-quinazolinyl)methylamino]propyl]tetrahydro-2-furancarbo xamide hydrochloride, alfuzosin (12), showed high selectivity for peripheral alpha 1-postjunctional adrenoceptors. At equiactive antihypertensive doses, its effect on the pressor response to postural changes in conscious dog was less marked than that shown by prazosin. In the light of these results, alfuzosin was selected for clinical evaluation.

Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action.

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.

Synthesis and analgesic activities of some (4-substituted phenyl-1-piperazinyl)alkyl 2-aminobenzoates and 2-aminonicotinates.

A series of (4-substituted phenyl-1-piperazinyl)alkyl 2-aminobenzoates and 2-aminonicotinates has been prepared and screened for analgesic and antiinflammatory properties in mice and rats. The tabulated results reveal several 2-(4-substituted phenyl-1-piperazinyl)ethyl 2-(7- or 8-substituted 4-quinolinylamino)benzoates to be six to nine times more potent analgesics than the reference compounds (glafenine and aminopyrine) and to possess minor antinflammatory activity. Compound 45, 2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl 2-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoate (antrafenine), showed marked analgesic activity, long duration of action, and excellent tolerance in pharmacological and toxicological studies, as well as in clinical trials.