A 3 dimensional model for 5-HT1A-receptor agonists based on stereoselective methyl-substituted and conformationally restricted analogs of 8-hydroxy-2-(dipropylamino)tetralin

Abstract

The enantiomers of cis- and trans-1,2,3,4,4a,5,10,10a-octahydro-9-hydroxy-1- propylbenzo[g]quinolines (10 and 11, respectively) and the enantiomers of trans-1,2,3,4,4a,5,6,10b-octahydro-10- hydroxy-4-propylbenzo[f]quinoline (12) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X-ray crystallography and molecular mechanics (MMP2) calculations. The compounds, which are conformationally restricted analogues of the potent 5-hydroxytryptamine (5-HT) receptor agonist 8-hydroxy-2- (dipropylamino)tetralin (8-OH-DPAT; 1) have been evaluated for central 5-HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats. In addition, we have evaluated the ability of these compounds and a number of previously reported analogues to displace [3H]-8-OH-DPAT from 5-HT1A-binding sites. The enantiomers of 12 behave as potent 5-HT1A-receptor agonists, whereas the octahydrobenzo[g]quinoline derivatives are much less potent or inactive. In general, the affinities of the compounds correlate well with their agonist potencies. The set of compounds under study is accommodated by a novel computer-graphics-derived model for 5-HT1A-receptor agonism. The model consists of a flexible pharmacophore and a partial receptor-excluded volume.

Application of desirability-based multi(bi)-objective optimization in the design of selective arylpiperazine derivates for the 5-HT1A serotonin receptor

“…Our previous interpretations are in agreement with the wellknown Mellin's two-point pharmacophore models [41] and threepoint Chilmonczyk's model [42]. Both of them consist of an aromatic ring and basic nitrogen (of the piperazine ring), but the three-point model also includes an oxygen atom forming a triangular configuration.…”

Extensive Rigid Analogue Design Maps the Binding Conformation of Potent N-Benzylphenethylamine 5-HT2A Serotonin Receptor Agonist Ligands

“…NaHCO 3 , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography, eluting with 1:1 EtOAc/ hexane, and the product was recrystallized from EtOAc/hexane to afford the product as a white powder (2.86 g, 72%); mp 100−102°C; 1 (±)-4-(2,5-Dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline (18). NaBH 3 CN (142 mg, 2.25 mmol) was added to a solution of 17 (100 mg, 0.38 mmol) in 10 mL of MeOH containing two drops of bromocresol green (1 N in MeOH), and the mixture was stirred at rt.…”

“…The free amines 9a and 9b were regenerated by treatment of the corresponding amides with super hydride. 18 …”

Structure and Activity of Membrane Receptors: Modeling and Computational Simulation of Ligand Recognition in a Three-Dimensional Model of the 5-Hydroxytryptamine (1A) Receptor

“…This compound is included in a series of 8-OH DPAT analogues examined for affinity [29] and for their pharmacological activity [9], Structure optimization of a JV-26 analogue, in which the propylammonium group was replaced by méthylammo nium, was carried out ab initio with the 6-31G basis set. These defined steric properties can be used in the con struction of a matching 5-HTiA recognition site, as de scribed below.…”

“…The resulting arrangement of the groups in the recogni tion site can explain the observed lower affinity of the enantiomer (1R,2S) of ALK-3 as compared with the ( 1 S,2R)-enantiomer (see 6 and 7 in figure 1, respective ly) [2,9,29], The (1R,2S)-enantiomer cannot form the hydrogen bond with site II because its methyl substituent at the Ci position points to the direction of site II. This situation is reversed for the ( 1 S,2R)~ enantiomer which does not have the methyl group oriented towards site II and thus can be recognized by the receptor through the proposed ion pair and hydrogen bond interactions.…”