Conformational and molecular mechanics studies of a new series of tricyclic ligands with affinity for either the dopamine D2 receptor or the 5-HT1A receptor, or both, has enabled us to elaborate considerably on previous pharmacophore models for these receptors. The new tricyclic ligands are either angular, 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives, or linear, 2,3,3a,4,5,9a-hexahydro-1H-benz[f]indole derivatives; they have either cis or trans ring junctions, and many of the ligands are resolved. In order to have X-ray crystal coordinates for every structural type, two additional crystal structures were determined: 14a, the trans-(+-)-6-hydroxy-3-(n-propyl) angular derivative as the hydrochloride, and (+-)-1,2,2a,3,4,8b-hexahydro-8-methoxy-2-(2-propenyl)-naphth[2,1- b]azetidine hydrochloride (16d). Several recently reported imidazoquinolinones with dopaminergic and serotonergic activities were also used in developing the models as were other known ligands which are conformationally constrained. A new method for determining intrinsic activity at the D2 receptor made consistent and reliable estimates of dopamine agonist, partial agonist, and antagonist activities available. The models explain these activities in terms of the 3-dimensional structural features of the ligands and their probable orientations at the D2 receptor site. They also explain why allyl and propyl analogs of some structures have very different affinities while affinities are quite similar for allyl and propyl analogs of other structures; at both receptors a particular orientation of the amine substituent in the binding site correlates with preference for allyl over propyl derivatives. Suggestions are made for enhancing selectivity at the 5-HT1A receptor or at the dopamine D2 receptor. An angular, cis, (3aR,9bS), 2-propyl, 9-hydroxy, 3-(n-propyl) analog should be selective for the 5-HT1A receptor. A linear, trans, (3aR,9aS), 7-hydroxy, 1-(2-propenyl) analog should be selective for the dopamine D2 receptor, and would be predicted to be an antagonist.

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

The synthesis and structure-activity relationships (SAR) of C-1- or C-3-substituted derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) are described. These analogs were synthesized via alkylation of the tetralone derivatives followed by reductive amination. All of the analogs were inactive at the dopamine D2 receptor. Among the 8-OMe or 8-OH C-1,N-disubstituted analogs synthesized, the cis analogs were more potent in the 5-HT1A binding assay than the corresponding trans analogs. However, in the case of 1-(cyclopropylmethyl)-N-n-propyl analogs, the trans isomer has a slightly higher 5-HT1A affinity than its cis counterpart. The order of binding potency for C-1 substitution was found to be allyl> hydroxymethyl > n-propyl > cyclopropylmethyl >> carbomethoxy. Interestingly, the 5-OMe analogs were found to be inactive in both the 5-HT1A and dopamine D2 binding assays. In the C-3 allyl-substituted analogs, 5-HT1A agonist activity was found to be considerably lower. In these examples, the trans analogs showed weak 5-HT1A binding activity whereas the cis analogs were inactive. Analogs with C-1,N,N-trisubstitution also showed a marked decrease in 5-HT1A binding affinity. Overall, the SAR study showed that cis C-1 substitution maintains the 5-HT1A agonist activity of 8-OH-DPAT whereas trans C-1 substitution displays somewhat diminished activity. On the other hand, the trans C-3 substitution shows modest agonist activity whereas cis C-3 substitution removes the activity completely.

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Der Prostaglandinester (I) wird in das 10‐Nor‐9,1 1‐seco‐Derivat (IIIa) übergeführt, das u.a. röntgenstrukturanalytisch charakterisiert wird.

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