A hypothetical model of the interaction of antipsychotic drugs with the dopamine receptor is described. This three-dimensional molecular model has been developed on the basis of plausible intermolecular interactions between pharmacophoric groups of diverse types of antipsychotic drugs and postulated amino acid side chain substituents of the receptor protein. Three essential binding sites (one possibly required for antagonism) and one lipophilic auxiliary binding site are identified. The geometry is defined via the three-dimensional structures of drugs exhibiting receptor activity, including (R)-apomorphine, (+)-dexclamol, and molindone (whose crystal structure has been determined). A new conformationally rigid pyrrolo[2,3-g]isoquinoline derivative has been designed to conform to the receptor model. The compound (+/-)-1 (2,6-dimethyl-3-ethyl-4,4a,5,6,7,8,8a,9-octahydro-4a,8a-trans-1H-pyrrolo[2,3-g] isoquinolin-4-one; Ro 22-1319) exhibits potent antipsychotic-like activity. The activity is stereospecific, residing in the (-) enantiomer, predicted and confirmed by X-ray crystal structure analysis of (-)-1.HCl to have the 4aR,8aR absolute configuration.
The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described. The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric groups to adopt conformations consistent with proposed bioactive conformations of the peptide. Compounds were synthesized by a stereoselective synthesis starting from L-glutamic acid. In a behavioral model of cognition in which TRH is active, the mimetics are potent, active compounds, exhibiting oral activity. One analog (26, (1S,3R,5(2S),5S)-5-[[5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-methyl]-5- [(1H-imidazol-5-yl)methyl]cyclohexaneacetamide) was radiolabeled for binding studies and evaluated in other binding assays and pharmacological tests. Competition binding of 26 vs [3H]MeTRH to rat brain slices suggests a two-site model for ligand binding with IC50's of 1 microM and 3 mM. Direct binding of [3H]-26 shows a biphasic curve with IC50's of 80 and 49 microM, respectively. Further studies would be needed to establish a link between the novel binding site(s) and the behavioral activity of 26 and TRH analogs.
The insect juvenile hormone, (+)-juvabione (la), has been synthesized from (+)-(4R,8/?)-/>-menth-len-9-ol, obtained by hydroboration of (ft)-(+)-limonene, via (2S)-[4-methyl-3-cyclohexen-(l/?)-yl]-6-methylheptan-4-one (10). Two routes for the oxidation of the allylic methyl group of 10, photochemical oxygenation and formation and opening of an oxirane via ß elimination, are described. This work establishes the absolute stereochemistry of la as R,S at the two asymmetric centers, in contradiction to the previously deduced R,R configuration. Syntheses of (-)-juvabione (3a), (+)-epijuvabione (4a), and (-)-epijuvabione ( 5) are also reported. The four diastereoisomers were very similar in all physical properties, except optical rotatory dispersion and circular dichroism which showed striking differences. These data are discussed.(11) J. F. Blount, B. A. Pawson, and G. Saucy, ibid., 715, 1016 (1969).(12) The absolute stereochemistry of (+)-todomatuic acid had been assigned5 based upon comparisons of the molecular rotations ([M]d) of the acid and its conversion products with sesquiterpenes of known absolute stereochemistry.
Condensation of l-arylsulfcmyl-2-methyl-4-hydroxy-2-butenes (1) with 1-chloroand l-bromo-3-methyl-5-(2,6,6-trimethylcyclohexen-l-yl)-penta-2,4-diene (2) to afford 1-hydroxy-3,7-dimethyl-4-arylsulfonyl-9-(2,6,6-trimethylcyclohexen-l-yl) nona-2,6,8-triene (3) and the subsequent elimination of sulfinic acid from 3 to give vitamin A alcohol has been studied. An efficient and stereoselective synthesis of halide 2 from vinyl-d-ionol (14) using HX in ether at low temperature has been achieved. The use of diethyl-and disilylamides with the p-tolyl sulfone compound lb and bromide 2b gave 3b in 83-84% isolated yield. Sodamide-ammonia-terf-butyl alcohol effected elimination of sulfinic acid in 3b to afford, after acetylation, vitamin A acetate in 75% yield from 3b. In a through process, crystalline, all-trans vitamin A acetate was obtained in 67-68 and 72-73% yield based on 14 and lb, respectively.
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