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With anaesthetized guinea pigs, the actions of moguisteine were tested on the cough reflex, the resting discharge of lung rapidly adapting receptors (RARs), RAR activity induced by aerosols of capsaicin, stimulation of RARs due to i.v. injection of capsaicin, and on the reflex responses to i.v. capsaicin. I.v. moguisteine (20 microg kg(-1)), compared with vehicle, decreased the spontaneous firing of RARs. Intragastric (i.g.) moguisteine (200 mg kg(-1)) had no effect on resting discharge. I.g. moguisteine depressed the cough response due to capsaicin aerosol (0.01(-1) mg ml(-1)) and significantly reduced the increased discharge of the RARs due to the aerosol. I.v. and i.g. moguisteine reduced the proportionate increase in RAR discharge due to i.v. capsaicin (50 microg kg(-1)). It did not appreciably affect the cardiovascular and respiratory responses to i.v. capsaicin, which presumably activated lung C-fibre receptors. We conclude that the antitussive action of moguisteine is mediated at least in part by a decrease in the excitatory response of RARs to tussive stimuli.

The synthesis of a novel class of antitussive agents is described. The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation. Ethyl 2-[(2-methoxyphenoxy)methyl]-beta-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan. The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents. The serendipitous discovery of the role played by the thiazolidine moiety in determining the antitussive effect promoted extensive investigations on these structures. This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2-[(2-methoxypheoxy)methyl]-3-[2-(acetylthio)acetyl]- 1,3-thiazolidine (18a) as an interesting lead compound. The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives. The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety. Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity. This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series. Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.

A series of 2-arylimidazo[2,1-a]isoquinolines (1-21), some 5,6-dihydro derivatives (22-28) and 2-phenyl-5H-imidazol[2,1]isoindole (29) were synthesized and tested for the pregnancy terminating activity in hamsters and rats. An efficient preparation of 2-arylimidazo[2,1-a]isoquinolines was devised. The isoquinolines having a 4-chlorophenyl (8), 4-bromophenyl (9), or a biphenylyl group (12) in the 2-position were the most potent compounds after subcutaneous administration. Compound 12 also showed good oral activity. The data obtained with the title compounds are compared with those of the corresponding triazolo [5,1-1]isoquinolines and isoindoles. The structure-activity relationships are discussed.

A series of 3-(1-iminoethyl)-4,5-cycloalkylpyridine-2,6-diol derivatives have been prepared from isoxazolo [5,4-b] pyridones. Some of these compounds had affinity for the benzodiazepine receptors in vitro and in vivo radioligand displacement assays. These compounds did not have any anticonvulsant properties and were not active in pharmacological tests predictive of antianxiety activity, but antagonised the anticonvulsant and muscle-relaxant effects of diazepam and had proconvulsant properties.

2,5-Dimethyl-1H-pyrrol-1-yl-butanoic acid (I) and 2,5-diethyl-1H-pyrrol-1-yl-butanoic acid (V) were synthesised as non basic analogues of 4-aminobutanoic acid (GABA) to investigate the influence of the pKa of the 4-nitrogen on the in vitro binding to GABA receptors. (I) displaced 3H-GABA from specific binding sites of synaptosomal membrane preparations from rat cerebellum with an IC50 of 0.5 microM and (V) with an IC50 of 0.4 microM. (I) was inactive in vivo in the bicuculline anticonvulsant test (mice i.p.). The authors conclude that a basic nitrogen is not necessary for the binding to the GABAergic receptors although the ensuing complex is likely to be pharmacologically ineffective.

The biological and the pharmacokinetic profiles of 2-(3-ethoxy-phenyl)-5,6-dihydro-s-triazole [5,1-a]isoquinoline (DL 204-IT) were explored in rats and hamsters at different stages of gestation (1st--11th day) after single and multiple (5 days) doses given in different vehicles (oily and aqueous) and by different routes of administration (s.c., i.m., i.v.). The effectiveness of the compound was demonstrated to be dependent on time of gestation, dose and vehicle. DL 204-IT did not show any pre-implantation activity. The optimal time for treatment was found to be immediately after the implantation of blastocysts. Time-course studies demonstrated that the anti-fertility action is slow and progressive with subsequent degeneration and reabsorption (rats and hamsters), or expulsion (only hamsters) of conceptuses. The biological and pharmacokinetic data show that with prolonged presence of the compound at the site of action (the utero-placental complex) lower doses are far more active in interrupting embryonal development than are much higher ones for shorter time periods.

A series of 3,6-disubstituted pyridazino[4,3-c]isoquinolines were synthesized and tested for their ability to inhibit the binding of [3H]diazepam to rat brain receptors in vitro. Compounds bearing a phenyl, 4-methoxyphenyl, or methyl group at position 3 and a dialkylamino group at position 6 showed the highest affinity in the binding assay and were subsequently evaluated for their anticonflict and anticonvulsant effects. All of these compounds (5a-1 and 5q) were active in the Vogel rat conflict procedure, but none prevented convulsions in mice induced either by metrazol or bicuculline. 3-Phenyl-6-pyrrolidinylpyridazino[4,3-c]isoquinoline (5d) with a Ki = 11.4 nM in the binding assay exhibited the best potency in the anticonflict assay (MED 5 mg/kg ip) and did not produce neuromuscular impairment at the highest dose tested (50 mg/kg ip).

The competition of some widely employed glucocorticoids with the binding of [3H]-promegestone, a highly potent synthetic progestagen, to uterine cytosol progestin receptors of the immature rat has been studied both in in vitro and ex vivo experiments. The relative binding affinities (RBA's) to progesterone were determined in vitro: fluocinolone acetonide greater than triamcinolone acetonide greater than betamethasone 17-valerate greater than prednisolone, betamethasone, triamcinolone and cortisol. After pretreating rats in vivo with progesterone or chlormadinone acetate (subcutaneously), a dose-dependent decrease in in vitro binding of [3H]-promegestone to uterine cytosol was evident. Similar decreases were obtained after pretreatment with some of the other glucocorticoids tested. Potency ratios to progesterone, arbitrarily set at 1.0, were: fluocinolone acetonide 86.7, triamcinolone acetonide 5.6, betamethasone valerate 4.1, chlormadinone acetate 2.6. Prednisolone, betamethasone, triamcinolone and cortisol were inactive. Both the in vitro and the ex vivo results clearly indicate that glucocorticoids interact with the uterine cytosol progestin receptor system, depending on their chemical structures; this interaction may account for some of their unwanted side-effects in the endocrine system. Moreover, this experimental system may prove to be a useful tool for evaluation of the progestational activities of glucocorticoids and other steroids, using the rat as an animal model.

Some 6-(alkylamino)-3-aryl-1,2,4-triazolo[3,4-a]phthalazines have been shown to displace diazepam from rat brain specific binding sites, in vitro, with Ki (nM) values comparable to those of reference benzodiazepines and to have anticonvulsant (pentylenetetrazole test, mice) and anticonflict activity (Vogel test, rat) in vivo. Separation between the doses causing anticonflict effects (Vogel test, rat) and those impairing motor coordination (rotarod test, rat) has been shown for N,N-bis(2-methoxyethyl)-3-(4-methoxyphenyl)-1,2,4-triazolo[3,4-a] phthalazin-6-amine (80). This compound, unlike diazepam, was inactive in counteracting the strychnine (mouse) and maximal electroshock (mouse) induced convulsions and in the "aggressive monkey" model. These differences from the classical benzodiazepines in the animal tests indicate that 80 may have some selective anxiolytic activity.

Some 13-aza-14-oxo prostaglandin analogues of PGF2 alpha, PGE2 and PGA2 have been synthetized in optically active form, starting from Corey's intermediate and evaluated for antifertility activity in the hamster. The C-15 absolute configuration was established and found critical for the biological activity, but unexpectedly the highest potency was always associated with the 15 epi derivatives. Among the PGF2 alpha analogues the 15 epi derivative was about one tenth as potent as PGF2 alpha. The preparation of a few 16-phenoxy 17,18,19,20 tetranor-derivatives led to more potent compounds with the p-fluorophenoxy analogue having the same potency as PGF2 alpha.

Some 2-aminoalkyl-8-chloro- and 2-aryl-1,2,4-triazolo[3,4-a]-phthalazine-3-(2H)-ones were synthesized and preliminarily tested in vitro and in vivo as potential benzodiazepine-receptor (BZRs) ligands. 2-Aryl-1,2,4-triazolo[3,4-a]-phthalazine-3(2H)-ones displaced in vitro 3H-diazepam (3H-DZ) from rat brain specific binding sites with Ki (nM) comparable to DZ and chlordiazepoxide used as reference compounds. The specific binding of the triazolones of this study was not enhanced in vitro by 4-aminobutyric acid (GABA) and in vivo they did not show any activity in counteracting the pentylenetetrazole (PTZ) induced convulsions (mice). One of these compounds (IV a) antagonized the effects of DZ in the bicuculline (BIC) induced convulsions test (mice) and the DZ induced muscle relaxant effects in the horizontal wire test.