7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602).

A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics.

Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.

Synthesis and pharmacological screening of new angiotensin converting enzyme inhibitors.

We report the preparation of a series of eight L-alanyl-L-proline derivatives and four L-proline derivatives. Their pharmacological activity as antihypertensive agents was examined with reference to changes in the contractile response to angiotensin I (AI), bradykinine (BK) and angiotensin II (AII). Compounds 1g, 1h and 2c were the most powerful when compared with known angiotensin-converting inhibitors such as captopril and enalapril, and were selected for further pharmacological study.

Synthesis of some N-benzhydrylpiperazine derivatives as calcium antagonists.

The preparation of a series of 24 N-benzhydrylpiperazine derivatives is described. Their efficacy as calcium antagonists was examined with reference to changes in the permeability of the cell membrane to extracellular and intracellular calcium. Compounds 14, 15, 17 and 19 were the most powerful when compared with known calcium antagonists such as cinnarizine, flunarizine, and aligeron ([1-diphenylmethyl)-4-(2-propenyl)]-piperazine), and were selected for further study.

[Structural requirements of guanine aminohydrolase (author's transl)]. / Requerimientos estructurales de la guanina aminohidrolasa de cerebro de cobaya.

Structural requirements of substrates and inhibitors of guinea-pig brain guanine aminohydrolase (GAH; E.C. 3.5.4.3), have been established by working with guanine analogs (8-azaguanine, 1-methylguanine, thioguanine and guanosine), purine precursors (5-aminoimidazole-4-carboxamide), purinic bases (xanthine, hypoxanthine, adenine and uric acid) and pyrimidinic bases (citosine, thymine and uracil). The need of the purine ring for the compounds to behave as substrate has been shown. The carbonyl group placed in position 6, plays an essential role in purine and pyrimidine binding to the enzymatic molecule. 5-aminoimidazole-4-carboxamide and allopurinol are enzyme inhibitors, while guanosine, thioguanine and 2,6-diaminopurine are not. Groups in positions 2, 6, 7 and 9 play a significant role in the union of the guanine molecule with guanine aminohydrolase.

[Liver and brain guinea-pig guanine aminohydrolase (author's transl)]. / Guanina aminohidrolasa de hígado y de cerebro de cobaya.

Guinea-pig brain guanine aminohydrolase (E.C. 3.5.4.3) (M = 120,000 +/- 5,000 daltons) only exhibited one active electrophoretic band; its mobility is similar with that observed for the guinea-pig liver molecular form III. Both forms appear to have coincident activity with pH, as well as an analogous thermal stability and Km values with different substrates showing a different behaviour with the molecular form I of guinea-pig liver enzyme. Brain guanine aminohydrolase and liver molecular form III have similar pK'a values suggesting the participation of histidine and cysteine (-SH) in the enzymatic catalysis. The competitive inhibition by p-chloromercuribenzoate may corroborate the intervention of the last-one.

[Molecular forms of guanine aminohydrolase (author's transl)]. / Formas moleculares de la guanina aminohidrolasa de hígado de cobaya.

Guanine aminohydrolase (E.C. 3.5.4.3) has been purified 11-fold from the supernatant fraction of guinea-pig liver homogenates in 0.25 M sucrose (centrifuged at 50,000 X g) through thermic denaturation at 60 degrees C and ammonium sulphate fractionation (30--60% saturation). The enzyme in the homogenates and purified preparations exhibited two Km values. In both preparations four enzymatic electrophoretic bands have been detected. Purified guanine aminohydrolase is chromatographically resolved on DEAE-sephadex in three components whose active forms appeared separately on their pherograms. The enzymatic form eluted at lower ionic strength has the least anodic mobility, is inhibited by guanine (4 X 10(-5) M) and presents only one Km value (1.5 X 10(-5) M). The enzymatic form eluted at greater ionic strength exhibits the highest anodic mobility, is also inhibited by guanine (7 X 10(-5) M) and its Km value seems to be 6.3 X 10(-6) M. Molecular weight of enzymatics forms determined by Sephadex G-200 chromatography, is 120,000 +/- 5,000. The preceding results, correlated with the chromatographic homogeneity of guanine aminohydrolase, purified in Sephadex G-100, suggests that the four molecular forms of the native enzyme may be considered as isozymes.