Conformational effects on the activity of drugs. 11. Stereostructural models for the direct activation of the alpha- and beta-adrenergic receptor.

Two kinds of cyclic analogues of norepinephrine (NE, 7) and isoprenaline (ISO, 8), in which the C(1)-C(2) side chain of these amino alcohols is incorporated in its preferred conformation in the ring of the 2-(3,4-dihydroxyphenyl)-morpholines 9 and 10 (2-DPMs) and in the ring of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 11 and 12 (3-DPPs), respectively, were synthesized and assayed for their adrenergic activity on various isolated preparations. The 2-DPMs and the 3-DPPs showed an alpha- and beta-agonist activity comparable to that of NE and ISO and to that of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 13 and 14 (2-ADTNs), which represent another kind of semirigid analogue of NE and ISO. Through a comparison of the stereo structures of the compounds examined and of their pharmacological properties, it was possible to suggest a spatial situation in which the pharmacophoric groups of the adrenergic drugs examined (aryl moiety, amine nitrogen, and alcoholic or ethereal benzylic oxygen) should interact at the receptor site. This spatial situation corresponds to the one found in the preferred conformation of NE and ISO. It was also possible to construct two theoretical three-dimensional molecular models that provide information about steric requirements for the direct activation of alpha- and beta-adrenoceptors, respectively.

Conformational effects on the activity of drugs. 7. Synthesis and pharmacological properties of 2-(p-nitrophenyl)-substituted morpholines.

A series of 1-(p-nitrophenyl)-2-aminoethanol derivatives and their morpholine analogues have been synthesized and pharmacologically investigated in order to confirm some pharmacological observations made with the N-isopropyl-substituted compounds. In agreement with the previously obtained results, the weak alpha-adrenergic-stimulating activity and the potentiating effect on the responses to norepinephrine found in the open-chain compounds persist in their corresponding semirigid cyclic analogues. The results are discussed in the light of common knowledge of the structure-activity relationships of alpha-adrenergic drugs.

Azaprostaglandin analogues. Synthesis and biological properties of 11-azaprostaglandin derivatives.

New nitrogen analogues of prostaglandins (11, 11a, 12, and 12a) have been synthesized starting from a 4,5-disubstituted 2-pyrrolidinone nucleus (5 and 5a) containing one side chain and a suitable functionality for elaborating the second one. These analogues had no better activity than natural prostaglandins in vitro [guinea pig ileum and trachea, rat stomach fundus strip, uterus and portal vein, ADP-induced guinea pig platelet-rich plasma (PRP) aggregation]. They similarly lacked any interesting activity in vivo [anesthetized rat blood pressure, stress, and acetylsalycilic acid (ASA) induced gastric lesions in rat].

Moguisteine: a novel peripheral non-narcotic antitussive drug.

1. The antitussive effects of moguisteine have been compared with codeine in several experimental models of cough in guinea-pigs and dogs. 2. Moguisteine and codeine dose-dependently (respective ED50 values are given in parentheses) inhibited cough induced in guinea-pigs by 7.5% citric acid aerosol (25.2 and 29.2 mg kg-1, p.o.), by 30 microM capsaicin aerosol (19.3 and 15.2 mg kg-1, p.o.), by mechanical stimulation (22.9 and 26.4 mg kg-1, p.o.) and by tracheal electrical stimulation (12.5 and 13.9 mg kg-1, p.o.). 3. Moguisteine was effective against cough induced by tracheal electrical stimulation in dogs (ED50 17.2 mg kg-1, p.o.); codeine was not tested because of its emetic effect. 4. After repeated dosing (12-15 days), moguisteine did not induce tolerance in either guinea-pigs or dogs. 5. Moguisteine did not interact with opiate receptors, since it did not show affinity for [3H]-naloxone binding sites and furthermore naloxone (5 mg kg-1, s.c.) did not antagonize its antitussive effects. 6. Moguisteine had no antitussive effect after i.c.v. administration (20 micrograms), whilst codeine (2-10 micrograms) and dextromethorphan (2.5-20 micrograms) were highly effective. 7. Our findings demonstrate that moguisteine is a novel peripherally acting non-narcotic antitussive agent, the mode of action of which remains to be elucidated fully.

Antipyretic and platelet antiaggregating effects of nimesulide.

Nimesulide strongly inhibited ex vivo platelet aggregation in guinea-pigs after both single and repeated (once daily for 5 days) oral dosing, irrespective of the aggregating agent used (adenosine diphosphate, arachidonic acid or collagen). Its potency was consistently greater than that shown by either ticlopidine or acetylsalicylic acid. In both oral and rectal administration, nimesulide proved to be more active and longer lasting than paracetamol in inhibiting fever induced in rats injected subcutaneously with brewer's yeast.

Effect of 7-chloro kynurenic acid on glycine modulation of the N-methyl-D-aspartate response in guinea-pig myenteric plexus.

The glycine modulation of the N-methyl-D-aspartate (NMDA) response in guinea-pig myenteric plexus was investigated by using D-serine and 7-chloro kynurenic acid as a glycine agonist and antagonist, respectively. D-serine caused a concentration-dependent enhancement of the NMDA response, an effect which was competitively inhibited by 7-chloro kynurenic acid (pA2 = 6.0). In addition, 7-chloro kynurenic acid induced a concentration-dependent, non-competitive inhibition of the NMDA response per se, even in the absence of added D-serine. This inhibition was fully reversed by exogenous D-serine, suggesting that this effect was also due to the occupancy of the glycine site. These results emphasize the usefulness of the guinea-pig myenteric plexus for studying the function of the NMDA receptor complex.

Effects of moguisteine on the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve in guinea pigs.

The study aimed to further demonstrate the peripheral antitussive properties of moguisteine. Firstly, the antitussive effect of moguisteine on the cough reflex induced by inhalation of citric acid aerosol was evaluated in conscious guinea pigs. Secondly, the effects of both moguisteine and codeine on the centrally mediated cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve were investigated in anesthetized guinea pigs. Moguisteine (2.5-10 mg/kg, intravenously, i.v.) reduced the cough reflex induced by 7.5% citric acid aerosol in a dose-dependent manner, with an ED50 value of 0.55 mg/kg. Both i.v. (0.5-4 mg/kg) and intracerebroventricular (i.c.v., 5-20 microg) injection of codeine dose dependently inhibited the cough reflex induced by afferent electrical stimulation of the superior laryngeal nerve; the ED50 values were 0.91 mg/kg and 7.90 microg, respectively. The inhibitory effect of codeine (4 mg/kg i.v.) was abolished by pretreatment with naloxone (2 mg/kg intraperitoneally). In contrast to codeine, neither i.v. (4 and 20 mg/kg) nor i.c.v. (20 microg) injection of moguisteine affected the cough reflex. These results suggest that the antitussive effect of codeine is mediated by central opioid mechanisms, whereas the antitussive effect of moguisteine is mediated by peripheral mechanisms.

Antitussive activity of moguisteine enantiomers in guinea-pigs and rats.

The antitussive effect of the R-(+)- and S-(-)-enantiomers of moguisteine were evaluated in comparison with the racemate in cough induced by 7.5% citric acid and 30 microM capsaicin aerosol in conscious guinea-pigs. No difference in potency was observed between moguisteine and the enantiomers. The oral ED50 values (with 95% confidence limits) for moguisteine, R-(+)- and S-(-)-enantiomers were respectively: 20.4 (12.9-26.6), 20.9 (14.9-26) and 21.6 (11.8-30.0) mg/kg-1 in cough provoked by citric acid and 17.7 (12.5-29.8), 18.9 (14.1-30.1) and 20.5 (15.1-36.6) mg/kg-1 in cough induced by capsaicin. The acute oral and intraperitoneal toxicities of the enantiomers and moguisteine in the rat are very similar. These findings suggest that the use of either enantiomer does not offer any advantage over the racemate.

FCE 20700, a cytoprotective PGE2 derivative, does not interfere with the antiinflammatory activity of indomethacin.

A study was made of the interaction between FCE 20700 (11-deoxy-13,14-didehydro-16(S)-methyl-PGE2 methylester) at a fixed dose of 250 mcg/kg and the ulcerogenic and antiinflammatory effect of indomethacin (I) on rat carrageenin paw edema. The combination tested showed the same antiinflammatory effect as I alone: potency ratio FCE 20700 + I/I was 1.03, demonstrating the lack of interaction between the two compounds. Moreover the gastric lesions in FCE 20700 + I treated rats were markedly reduced, allowing the dosage of I to be increased by about three times without increasing its ulcerogenic effect.

Stereoselective pharmacokinetics of moguisteine metabolites in healthy subjects.

We studied the pharmacokinetics of moguisteine, a racemic non-narcotic peripheral antitussive drug, in 12 healthy male subjects after a single oral administration of 200 mg. The unchanged drug was absent in plasma and urine of all subjects. Moguisteine was immediately and completely hydrolyzed to its main active metabolite, the free carboxylic acid M1. Therefore, we evaluated the kinetic profiles of M1, of its enantiomers R(+)-M1 and S(-)-M1, and of M1 sulfoxide optical isomers M2/I and M2/II by conventional and stereospecific HPLC. Maximum plasma concentrations for M1 (2.83 mg/l), M2/I (0.26 mg/l) and M2/II (0.40 mg/l), were respectively reached at 1.3, 1.6 and 1.5 h after moguisteine administration. Plasma concentrations declined after the peak with mean apparent terminal half-lives of 0.65 h (M1), 0.88 h (M2/I) and 0.84 h (M2/II). Most of the administered dose was recovered in urine within 6 h from moguisteine treatment. The systemic and renal clearance values indicated high renal extraction ratio for all moguisteine metabolites, and particularly for M1 sulfoxide optical isomers. Plasma concentration-time profiles and urinary excretion patterns for M1 enantiomers R(+)-M1 and S(-)-M1 were quite similar. Thus, for later moguisteine pharmacokinetic evaluations the investigation of the plasma concentration-time curve and the urinary excretion of the sole racemic M1 through non-stereospecific analytical methods may suffice in most cases.

Effect of indoprofen on prostaglandin and thromboxane A2 synthesis in the guinea pig lung.

Indoprofen has been studied in vitro as a possible selective inhibitor of thromboxane-synthetase in guinea pig lungs perfused with arachidonic acid. Indoprofen does not show selectivity of action since KB values for prostaglandin and TXA2 synthesis are not significantly different. Indoprofen might therefore act at the cyclooxygenase level as has already been demonstrated for indomethacin.

Tartrazine and prostaglandin-system.

Tartrazine, a dye largely employed for colouring foods, drinks, drugs and cosmetics, induces in some aspirin-sensitive subjects a bronchoconstriction similar to that caused by aspirin and other nonsteroidal anti-inflammatory drugs. The interference of tartrazine on prostaglandin system of guinea pig lungs perfused with arachidonic acid has been studied. This compound is able to inhibit in the same manner the formation both of prostaglandins and of thromboxane A2 acting at the cyclooxygenase level as has already been demonstrated for aspirin and indomethacin. Preliminary experiments on aspirin asthmatic patients treated or not with tartrazine are discussed.

Effect of prostaglandins on the increased corticosterone output induced by caffeine in the rat.

The effect of prostaglandins on the increase of corticosterone output induced by caffeine was investigated in rats. PGE2 and some synthetic prostaglandins (11-deoxy-derivatives), which stimulate steroid output in vitro, enhanced the effect of caffeine. Pretreatment with indomethacin inhibited the effect of caffeine.

Effects of prostacyclin on aspecifically and specifically induced bronchoconstriction in asthmatic patients.

The efficacy of prostacyclin in preventing aspecifically and specifically induced bronchoconstriction was evaluated in a single-blind cross-over study in 3 groups of asthmatic patients. Prostacyclin was given by inhalation in doses of 250 microgram in women and 500 microgram in men. Ultrasonic mist of H2O (group 1), physical exercise on cycloergometer (group 2) and pneumoallergens (group 3) were used as bronchial stimulant agents. Prostacyclin gave a very good protection in the first 2 groups, but was ineffective in the third. An increase in heart rate was observed immediately after the inhalation of prostacyclin: this effect was particularly evident in women in whom a significant decrease in diastolic pressure was noted too.

The effect of different prostaglandins on gastric mucosal intracellular second messenger system in the rat.

After an oral administration of 100 micrograms/kg dose, the investigated prostaglandins: PGF2 alpha, PGE2 and a synthetic PGE2 derivative: FCE-20700, exerted a significant effect on cAMP and cGMP content of both parts (antral and fundic) of gastric mucosa, resulting in an elevated cAMP/cGMP ratio, while 6-keto-PGF1 alpha, the stable break-down product of prostacyclin, was inactive. Since the above-mentioned phenomenon seems to be proportionate to the cytoprotective (anti-ulcerogenic) property of the investigated prostaglandins, this cAMP/cGMP ratio "shift" is interpreted as a probable (molecular) sign of the reparative, (anti-ulcerogenic) processes.

Effects of naftopidil on some urodynamic parameters and arterial blood pressure in comparison with prazosin in conscious rats.

Naftopidil, an alpha 1-adrenergic antagonist, was orally tested in comparison with prazosin, in a rat cystomanometric model to evaluate the effect on the bladder volume capacity (BVC), the micturition pressure (MP) and the mean arterial blood pressure (MAP), contemporaneously recorded to evaluate the selectivity of action. Naftopidil induced a clearcut increase of BVC and a decrease of MP without lowering MAP at 6.25 mg kg-1 p.o.. Prazosin was inactive on BVC, decreased MP and induced a significant decrease of MAP at 1.56 mg kg-1 p.o. Naftopidil could offer an advantage when compared with prazosin.

Comparative toxicology of two enantiomers of the peripherally acting non-narcotic antitussive drug moguisteine.

Moguisteine (R,S(+/-)-2-(2-methoxyphenoxy)-methyl-3-ethoxycarbonylacetyl-1,3-t hiazolidine, CAS 119637-67-1), a new peripheral non-narcotic antitussive drug, is a racemate composed of an equimolar mixture of R(+) and S(-) enantiomers (BBR 2221 and BBR 2222, respectively). Since in some cases the use of only one enantiomer instead of a racemate may increase the efficacy and/or the tolerability of a compound, moguisteine enantiomers were submitted to toxicological evaluation. Given in a single oral (gavage) or intraperitoneal administration to mice and rats, both moguisteine enantiomers show very low general toxicity. Administered by gavage to rats and dogs for four consecutive weeks, BBR 221 and BBR 2222 are tolerated at up to the dose of 240 mg/kg/day in both sexes with no appreciable toxic changes. Finally, the mutagenicity tests show that both enantiomers are devoid of any mutagenic potential both in vitro and in vivo. Considering the overall results of the toxicological studies and comparing them with the data obtained from the previously performed studies with the racemate moguisteine, it can be affirmed that no differences can be identified between the two enantiomers and the racemate moguisteine. These findings justify the development of moguisteine as a racemate since neither enantiomer should offer any advantage over the racemate.