Dopamine D(3) receptor antagonists. 1. Synthesis and structure-activity relationships of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans.

5,6-Dimethoxy-2-(N-dipropyl)-aminoindan (3, PNU-99194A) was found to be a selective dopamine D(3) receptor antagonist with potential antipsychotic properties in animal models. To investigate the effects of nitrogen substitution on structure-activity relationships, a series of 5,6-dimethoxy-N-alkyl- and N-alkylaryl-substituted 2-aminoindans were synthesized and evaluated in vitro for binding affinity and metabolic stability. The results indicate that substitution at the amine nitrogen of the 2-aminoindans is fairly limited to the di-N-propyl group in order to achieve selective D(3) antagonists.

Common discriminative stimulus properties in rats of muscarinic antagonists, clozapine and the D3 preferring antagonist PNU-99194a: an analysis of possible mechanisms.

Dopamine D3 receptors have been implicated in the aetiology of schizophrenia and the actions of antipsychotic drugs. The initial studies reported here assessed the involvement of such receptors in the in vivo actions of the atypical antipsychotic clozapine and the putative D3-preferring antagonist PNU-99194A in drug discrimination assays. Rats trained to discriminate clozapine consistently generalized to PNU-99194A in two separate studies.

Structure-activity relationships in the 8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole ring system. 2. Effects of 8-amino nitrogen substitution on serotonin receptor binding and pharmacology.

A series of analogs of the potent and selective 5-HT1A agonist 8-(di-n-propylamino)-6,7,8,9-tetrahydro-3H-benz[e]indole-1-carbaldehyde (2b) (OSU191) was prepared in which the dipropylamino group was modified to bear a variety of substituents. These compounds were evaluated for both in vitro and in vivo effects, including the establishment of a receptor binding profile for these analogs at the 5-HT1A, dopamine D-2, dopamine D-3, 5-HT1D alpha, and 5-HT1D beta sites. Several of the analogs were evaluated for their biochemical effects in reserpinized rats, specifically with regard to in vivo changes in brain levels of 5-HTP and DOPA.

C-9 and N-substituted analogs of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3- propyl-1H-benz[e]indole-9-carboxamide: 5-HT1A receptor agonists with various degrees of metabolic stability.

Closely related analogs of the 5-HT1A receptor agonist cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9- carboxamide (1, U93385) were synthesized and pharmacologically evaluated. 9-Carboxamide analogs with varied nitrogen substitution (R2) were synthesized, and their serotonergic activity was evaluated in vitro and in vivo. Many of these compounds were incubated in the presence of rat hepatocytes, and the metabolic stability in vitro was compared to that of compound 1.

Differential effects of dopamine D2 and D3 receptor antagonists in regard to dopamine release, in vivo receptor displacement and behaviour.

To establish possible functional differences between the dopamine D2 and D3 receptor we investigated the relation between the ability, for a set of nine mixed dopamine D2 and D3 receptor antagonists, to displace N, N-dipropyl-2-amino-5,6-dihydroxy tetralin (DP-5,6-ADTN) from striatal binding sites and the subsequent behavioural consequences in vivo. Dopamine D2 receptor preferring antagonists are powerful displacers of DP-5,6-ADTN from the striatum. Maximal displacement is followed by strong hypomotility.

Synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro- 3-propyl-1H-benz[e]indole-9-carboxamide: a potent and selective 5-HT1A receptor agonist with good oral availability.

The synthesis and biological activity of cis-(3aR)-(-)-2,3,3a,4,5,9b- hexahydro-3-propyl-1H-benz[e]indole-9-carboxamide ((-)-3a), U93385, is described. The cis racemate and its enantiomer as well as the corresponding trans enantiomers were also synthesized and evaluated. The synthesis of these analogs was achieved via either a four-step conversion of the 9-hydroxy precursor into 9-carboxamide or an alternative synthesis using the (R)-alpha-methylbenzyl group as the chiral auxiliary.

Comparison of 5-HT1A and dopamine D2 pharmacophores. X-ray structures and affinities of conformationally constrained ligands.

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).

Centrally acting serotonergic and dopaminergic agents. 2. Synthesis and structure-activity relationships of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole derivatives.

The conformationally restricted linear tricyclic analogs of 5- and 8-hydroxy-2-(di-n-propylamino)-tetralins were investigated for their serotonergic and dopaminergic properties. These cis and trans analogs of 2,3,3a,4,9,9a-hexahydro-1H-benz[f]indole (3), where a five-membered ring is fused between the nitrogen and C-3 carbon of 2-aminotetralin, were synthesized from 5-methoxy- and 8-methoxytetralones. The enantiomers of trans-5-methoxy-N-n-propyl and -N-allyl analogs were obtained via fractional recrystallization of their di-p-toluoyl-L (or D) tartaric acid salts.

Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.

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.

Centrally acting serotonergic agents. Synthesis and structure-activity relationships of C-1- or C-3-substituted derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin.

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.

The dopamine D3-receptor: a postsynaptic receptor inhibitory on rat locomotor activity.

We report on the pharmacological effects of the 20 fold D3 vs. D2 dopamine receptor preferring compound U99194A. It is shown that U99194A increases rat locomotor activity at doses that do not increase release or utilisation of dopamine in the striatum or the nucleus accumbens significantly.