The synthesis and analgesic testing of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]cyclohexanol (1) are described. Prior (SAR) studies led us to conclude that the pyran ring of 9-nor-9 beta-hydroxyhexahydrocannabinol (HHC) was not necessary for the expression of biological activity in this series of cannabinoids. Analysis of models and the use of molecular mechanics calculations suggested that a simpler compound, such as 1, would possess the biological activity of HHC. Compound 1 was prepared in nine steps from [3-(benzyloxy)phenyl]acetonitrile (2). Biological testing in five models of pain shows that compound 1 and morphine are equally potent as analgesics and demonstrates that the pyran ring of HHC is not necessary for biological activity. Further simplification of 1 was pursued by the synthesis of 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-2-pentanol (17), but this derivative exhibits significantly reduced analgesic activity.
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.
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.
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.
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.
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