Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties.

Angelicin and some of its derivatives are naturally occuring compounds which show interesting photobiological properties. In this review various aspects of angelicin and its derivatives have been reported. The natural occurrence and the chemical synthesis both of naturally occurring and synthetic angelicins have been reviewed. Photochemical and photophysical properties of angelicins have been considered with particular reference to the capacity to generate active forms of oxygen, photoreactions with nucleic acids, proteins and unsaturated fatty acids. Photobiological effects have been considered: skin phototoxicity, antiproliferative effects, genotoxicity, ability to induce hemolysis in erythrocytes, inactivation of prokaryotic and eukaryotic microorganism and of viruses. The ability of some angelicins to induce photocarcinogenesis has been reviewed as well as in the activity as photochemotherapeutic agents.

Synthesis and neuroleptic activity of isomeric thieno(1,4)benzothiazines.

To investigate the influence of electronic properties of the tricyclic thiazine system on neuroleptic activity, a series of the isomeric N-dimethylaminopropylthienobenzothiazines was synthesized. All compounds were screened for neuroleptic activity in mice and rats. For the active compounds lowest active doses in the antiamphetamine test were determined. Activity appeared to be dependent on the mode of annelation of the thiophene molecule: compunds bearing the same substituent and side chain with the thiophene molecule in 2,3 and 3,4 annelation were active, while those compounds with a 3,2 annelation seemed to be devoid of activity at the given dose.

Analgesic and tranquilizing activity of 5,8-disubstituted 1-tetralone Mannich bases.

5,8-Disubstituted 1-tetralone Mannich bases represent semirigid variants of classical (i.e., chlorpromazine) neuroleptic agents. 8-Chloro-5-methoxy-2-morpholinomethyl-1-tetralone exhibits neuroleptic potency in the thiothixene range in animal models. Of greater potential interest, however, is the analgesic potency of the 8-chloro-5-methoxy-2-pyrrolidinomethyl analogue which was in the morphine range. This compound did not induce tolerance nor was its activity reversed by naloxone. Structure-activity relationships of the series are discussed.

Neuroleptic agents of the benzocycloheptapyridoisoquinoline series. 1. Syntheses and stereochemical and structural requirements for activity of butaclamol and related compounds.

The syntheses and the structural and stereochemical requirements for antagonism of (+)-amphetamine-induced sterotypy are described for a series of benzocycloheptapyridoisoquinoline derivatives. One of these compounds, (plus or minus)-(4a,13b-trans)[3(OH),13b(H)-trans[-3-tert-butyl-2,3,4,4a,8,9,13b,14-octahydro-1H-benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3ol hydrochloride (butaclamol hydrochloride, USAN), is currently being studied in man. The relationship between structure and antiamphetamine activity in this class of compounds is discussed.

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen).

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).

Synthesis of certain benzo- and pyridodiazepines likely to possess tranquilizing effect.

The synthesis of certain 1.5-benzodiazepinediones, some of their oxygen-free analogues and a number of the 7-nitro derivatives is described. Condensation of 3.4-diaminopyridine with diethylmalonate instead of affording the expected pyridodiazepine, yielded an imidazopyridine, the structure of which was inferred from spectral data Nevertheless, the pyridodiazepine was obtained by condensing the diamino-heterocycle with malonyl dichloride.