Synthesis, modelling and NK1 antagonist evaluation of a non-rigid cyclopropane-containing analogue of CP-99,994.

A non-rigid cyclopropane-containing diamine analogue of CP-99,994 was synthesised and was found to have only moderate NK1 receptor binding affinity. Molecular dynamics calculations of the conformational space of the former compound gave good correlation between observed activity and a recently published pharmacophore model, lending predictive value to the latter.

Synthesis and anticonvulsant properties of triazolo- and imidazopyridazinyl carboxamides and carboxylic acids.

Analogues of 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine PC25 containing amide or carboxylic acid function were synthesized and tested for anticonvulsant activity. The compounds having the imidazole ring substituted with an amide group have been found to be generally more active against maximal electroshock-induced seizures in mice (15.2 < or = ED50 < or = 37.5 mg kg(-1) orally). Furthermore, maximum activity was generally associated with a 2,6-dichlorobenzyl substitution pattern. 3-Amido-7-(2,6-dichlorobenzyl)-6-methyltriazolo[4,3-b]pyridazine 4b was also protective in the pentylenetetrazole-induced seizures test (ED50 = 91.1 mg kg(-1) orally) and blocked strychnine-induced tonic extensor seizures (ED50 = 62.9 mg kg(-1) orally). Moreover, calculated electrostatic isopotential maps of the whole active compounds were quite similar and, consequently, could be associated to optimum anticonvulsant activity.

Pharmacophore requirements in new series of pyridazinyl alkanoic acids, N-[(pyridazin-2-yl) alkyl] succinyl and glutaryl amides, inhibitors of thromboxane A2 biosynthesis.

New series of 5-benzyl-6-methyl-4-oxo pyridazin-2-yl alkanoic acids, N-[(pyridazin-2-yl)alkyl] succinyl and glutaryl amides have been synthesized and evaluated in vitro as TXA2 biosynthesis inhibitors. The experiments were carried out using arachidonic acid (32.8 microM) as a substrate and horse platelet microsomes as sources of TXA2 synthase. The presence of TXB2, a stable metabolite of TXA2, was determined by RIA. The potency of active compounds (1.10(-4) < IC 50 < 1.10(-6) M) greatly depends on the length of the chain at the N-2 position on the pyridazine ring. Furthermore, enzyme inhibition in vitro is increased with the presence of a halogen atom on the aromatic moiety of the benzyl group at C-5. Compound 4f having a pentanoic side chain and a 4-fluoro benzyl moiety was the most active derivative with an IC50 value of 6.69 x 10(-6) M. Molecular modelling studies were done on all the synthesized pyridazinones and on prostaglandin H2 (PGH2) suggesting spatial features and volumes of TXA2 synthase pharmacophore mode in these series of derivatives.

Synthesis and pharmacological evaluation in mice of new non-classical antinociceptive agents, 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones.

Several 5-(4-arylpiperazin-1-yl)-4-benzyl-1,2-oxazin-6-ones have been synthesized and tested for analgesic activity in a visceral pain model (phenylbenzoquinone-induced writhing test = PBQ test). A good correlation has been found between the antinociceptive effects of drugs and both their lipophilic and steric properties. The most active derivatives 5c and 5f, with intraperitoneal ED50 values of 10.5 and 10.3 mg kg-1 respectively, were more extensively investigated by evaluating their analgesic activity in a somatosensory pain model (hot plate test), as well as their sedative properties. Furthermore, naloxone suppressed the effect of 5c and 5f in the PBQ test, though these derivatives were ineffective to potentiate morphine analgesia. Pretreatment with yohimbine did not significantly attenuate the analgesic effects of 5c and 5f. In addition, pretreatment with 5-hydroxytryptophan associated with carbidopa also failed to potentiate the antinociceptive effects of 5c and 5f. So, a part of the analgesic activity of 5c and 5f seems to be related to an opioidergic mechanisms, especially at the mu receptor level. Molecular modeling studies performed on the opiate drug morphine and on the most stable conformer of 5f showed structural similarities between these two molecules.

Synthesis and anticonvulsant properties of new benzylpyridazine derivatives.

Several 3-substituted pyridazines and a series of imidazo- and triazolopyridazines were synthesized and tested for anticonvulsant activity against maximal electroshock-induced seizures in mice. The most active derivatives, 3-ureidopyridazine 7 and triazolopyridazines 16, 18, 21, and 25 with oral ED50's that ranged from 6.2 to 22.0 mg/kg, were more extensively investigated by evaluating their ability to prevent chemically induced seizures and were compared with phenytoin, phenobarbital, sodium valproate, carbamazepine, and diazepam. 3-amino-7-(2,6-dichlorobenzyl)-6-methyltriazolo-[4,3-b]pyridazine (25) was also protective in the pentylenetetrazole-induced seizures test (ED50 = 76 mg/kg per os) and blocked strychnine-induced tonic extensor seizures (ED50 = 34.5 mg/kg per os). Furthermore, derivative 25 showed anticonvulsant effects on bicuculline- and yohimbine-induced seizures tests in mice. All these results suggest that the pharmacological activity of 25 is partly due to modifications of glycinergic and GABAergic transmission. Moreover, molecular modeling studies based on the antiepileptic drug lamotrigine and the most stable conformer of 25 show structural similarities between these two molecules. This conformer also agrees with the electronic tolerances and volume of benzodiazepine pharmacophore models.