Seven enantiomeric pairs of N-alkyl analogues of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) have been synthesized and evaluated pharmacologically (biochemistry and behavior) in order to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulkier than n-propyl. Likewise, the S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors. In the total series, (S)-(-)-3-PPP [(S)-12] seems to be the most interesting compound both from the theoretical and the therapeutical point of view, possibly attenuating DA function in two different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.

N-Substituted analogues of trans-7- and trans-9-hydroxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline (trans-7- and trans-9-OH-OHBQ) were tested for dopamine (DA) D2 receptor affinity by using in vitro [3H]spiperone and in vivo 5,6-di-n-Pr-ADTN binding assays. Potencies at central pre- (auto-) and postsynaptic DA receptors were determined by a biochemical and a behavioral method, respectively. Corresponding data were included for analogous, resolved 3-(3-hydroxyphenyl)piperidines and a few other substituted, racemic 3-phenylpiperidines. Beside the central dopaminergic effects of these compounds, previously reported sigma receptor affinity data [[3H]-(+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine; [3H]-(+)-3-PPP] were also taken into account for a comparison of the structure-activity/affinity relationships of these compounds at these two receptor types. Larger N-substituents in both phenylpiperidines and OHBQs increase both pre- and postsynaptic dopaminergic activity. An n-propyl group gives high dopaminergic efficacy at both receptor sites (pre- and postsynaptic) in all series. However, even higher dopaminergic potency is observed for trans-7-OH-OHBQs and (S)-3-(3-hydroxyphenyl)piperidines with N-substituents larger than n-propyl. In contrast, trans-4-n-Bu-9-OH-OHBQ is inactive, and (R)-3-(3-hydroxyphenyl)-N-n-butylpiperidine is less active at central DA receptors than its corresponding n-propyl analogue. This implies interesting differences in N-substituent sensitivity for the different classes of compounds with respect to the direction of their respective N-substituents at the drug-receptor interaction. The stereochemical and steric demands for sigma receptor affinity are much less stringent. The general trend is that, up to a certain size, the more lipophilic the N-substituent, the higher the affinity for sigma receptor sites.

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ChemInform Abstract Cyclopropanation reaction of the trans-cinnamate (I) with diazomethane (II) followed by saponification of the ester yields the trans-phenylcyclopropanecarboxylic acid (III). Subsequent Curtius rearrangement using diphenyl azidophosphate (IV), followed by acidic hydrolysis of the intermediate carbamate, forms the hydrochloride (V) of the trans-amine. N,N-Dialkylation and cleavage of the methoxy groups with HBr produce the amino(hydroxyphenyl)cyclopropanes (VIII). The related compounds (X) are prepared in a similar manner. In order to prepare pure enantiomers the acid (III) is converted to the chloride and then treated with a chiral amino alcohol to form a mixture of diastereomeric amides which are separated by chromatography, saponified and then converted to optically pure enantiomers of (VIII).

Structure-Activity Relationships in the 8- 7,8,indole Ring System. Part 2. Effect of 8-Amino Nitrogen Substitution on Serotonin Receptor Binding and Pharmacology.-In continuation of the preceding paper a series of nonformylated (I) and formylated analogues (II) (ca. 30 examples) of the potent and selective agonist (IIa) is prepared in which the dipropylamino group is modified. The substituent influence of these compounds (as racemic mixtures or in some cases in optically pure form) on the in vitro receptor binding with respect to the 5-HT1A, 5-HT1Dα, 5-HT1D. beta., and dopamine D2 and D3 sites as well as their in vivo pharmacology in reserpinized rats is investigated. Nearly all of these analogues exhibit excellent activity for the 5-HT1A receptor and good selectivity for serotonine over dopamine sites. Generally, the (R)-enantiomers possess the superior receptor affinity, and those analogues having a good affinity for 5-HT1A also show clear agonist pharmacology. -(ENNIS, M. D.; STJERNLOEF, P.; HOFFMAN, R. L.; GHAZAL, N. B.; SMITH, M. W.; SVENSSON, K.; WIKSTROEM, H.; HAADSMA-SVENSSON, S. R.; LIN, C.-H.; J.