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Ethyl beta-carboline-3-carboxylate (beta CCE), a benzodiazepine antagonist, was found to increase basal levels of cyclic GMP in rat cerebellum. beta CCE also augmented the elevation of cyclic GMP concentrations induced by isoniazid, in contrast to diazepam which blocked this effect of isoniazid. Administration of beta CCE and diazepam together cancelled each other's effect on the elevation of cyclic GMP levels after isoniazid. Ro 15-1788, another potent benzodiazepine antagonist, was found to have virtually no effect on cyclic GMP levels in naive or isoniazid-treated rats. Ro 15-1788 antagonized diazepam's lowering of the elevation of cyclic GMP content of cerebellum after isoniazid. Ro 15-1788 also blocked the increase in cyclic GMP levels elicited by beta CCE, indicating that this effect of beta CCE involves its interaction at benzodiazepine receptors. Some pharmacological actions of beta CCE might be based on hindering GABA transmission.

A series of 5-aryltetrahydro-gamma-carbolines was prepared by a novel N-arylation procedure and tested for neuroleptic activity in a rat antiamphetamine model. The systematic exploration of structural parameters leading to 8-fluoro-5-(4-fluorophenyl)-2-[4-hydroxy-4-(4-fluorophenyl)butyl]-2,3,5-tetrahydro-1H-pyrido[4,3-b]indole (CP-36,584, flutroline), a potent and long-acting neuroleptic compound, is described. These semirigid compounds provide a new, structurally distinct series with which to probe the conformational requirements for potent activity at the dopamine receptor.

A series of trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5, 9b-hexahydro-1H-pyrido[4,3-b]indoles with various N-2 substituents has been prepared and tested for neuroleptic activity [( 3H]spiroperidol binding and amphetamine antagonism). Several members of this series showed exceptional in vivo potency, especially the hydantoin derivatives 27-30. Resolution into the enantiomers showed that neuroleptic activity is associated with the 4aS,9bS absolute configuration. These rigid neuroleptics have been correlated with other rigid neuroleptics [(+)-dexclamol, Ro 22-1319] and can serve to further define the topography of the dopamine receptor.

Substitution of position 2 of the 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole nucleus with omega-carboxamidoalkyl substituents leads to compounds with exceedingly potent neuroleptic activity in in vitro and in vivo models. Although duration of activity is not as long as that of the analogous 4-hydroxy-4-(4-fluorophenyl)butyl derivatives reported previously, the absolute potency in vivo is greater. The ability of these compounds to bind with great affinity to dopamine (DA) receptors further defines the nature of the DA receptor auxiliary binding site as a hydrogen-bond donating site in addition to or instead of a lipophilic site as has been previously proposed.

The preparation and testing of the two racemic diastereoisomers and the four optically active enantiomers of the title compound in in vitro and in vivo models for determining potential antipsychotic activity are described. Both racemic diastereoisomers and two of the four chiral enantiomers are potent and long-acting neuroleptic compounds.

Compounds derived from 4a,9b-trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4, 3-b]indole are consistently efficacious in displacing [3H]spiroperidol from striatal dopamine receptors in vitro. Derivatives bearing substituents at position 2, particularly those derived from butyrophenone moieties, are exceptionally potent in vivo. Compounds from the corresponding 4a,9b-cis series are substantially less potent in both in vivo and in vitro assays of neuroleptic activity. Although the cis and trans derivatives have, in some conformations, similar basic nitrogen atom to aromatic ring separations of about 5.1 A, the distance at which the basic nitrogen atom lies above or below the plane of the aromatic ring differs substantially between the two series. Consideration of these results in terms of this and earlier work indicates that the out-of-plane distance for the basic nitrogen in neuroleptic molecules may range from about 0 to about 0.90 A but may be optimized at about 0.55 A.