N-substituted 1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolines and 3-phenylpiperidines: effects on central dopamine and sigma receptors

J Med Chem. 1987 Dec;30(12):2169-74. doi: 10.1021/jm00395a002.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects*
  • Male
  • Motor Activity / drug effects
  • Phenanthrenes / pharmacology*
  • Piperidines / pharmacology*
  • Quinolines / chemical synthesis
  • Quinolines / pharmacology*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / drug effects*
  • Receptors, Dopamine D2
  • Receptors, Opioid / drug effects*
  • Receptors, sigma
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Phenanthrenes
  • Piperidines
  • Quinolines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Opioid
  • Receptors, sigma
  • HW 165