Resolved cis-10-hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b- octahydrobenzo[f]quinoline : central serotonin stimulating...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Structural Chemistry

Background:

• cis-10-Hydroxy-4-n-propyl-1,2,3,4,4a,5,6,10b -octahydrobenzo[f]quinoline (4) is a centrally acting serotonin (5-HT) receptor agonist with moderate potency.
• Structural similarities exist between compound 4 and cis-(1S,2R)-8-hydroxy-1-methyl-2-(di-n-propylamino)tetralin (2), a more potent 5-HT receptor agonist.

Purpose of the Study:

• To prepare and pharmacologically test the enantiomers of compound 4.
• To compare the stereochemistry of the active enantiomers of compounds 4 and 2.
• To elucidate the absolute configuration and conformational preferences of compound 4 and its analogues.

Main Methods:

• Resolution of a precursor (6) to obtain enantiomers of compound 4.
• Pharmacological testing of enantiomers.
• Single-crystal X-ray analysis of precursor (+)-6.
• Conformational analysis using molecular mechanics (MM2) calculations on N-methyl analogues (3 and 7).

Main Results:

• The 4aR,10bS enantiomer of compound 4 was identified as the more active isomer, coinciding stereochemically with the active enantiomer of compound 2.
• Absolute configuration was determined via X-ray crystallography of (+)-6.
• MM2 calculations indicated a preference for the N-equatorial conformation in both ammonium and free amine forms, consistent with X-ray data.

Conclusions:

• The stereochemical requirements for potent serotonin (5-HT) receptor agonism are conserved between the octahydrobenzo[f]quinoline and tetralin series.
• The lower potency of cis-(4aR,10bS)-4 may be attributed to an unfavorable orientation of the nitrogen lone pair or ammonium hydrogen.
• Further investigation into the structure-activity relationship is warranted, particularly concerning the trans enantiomer of compound 5.