Structural determinants of σ receptor affinity

B. L. Largent, H. Wikstrom, A. L. Gundlach, Solomon H Snyder

Research output: Contribution to journalArticle

Abstract

The structural determinants of σ receptor affinity have been evaluated by examining a wide range of compounds related to opioids, neuroleptics, and phenylpiperidine dopaminergic structures for affinity at σ receptor-binding sites labeled with (+)-[3H]3-PPP. Among opioid compounds, requirements for σ receptor affinity differ strikingly from the determinants of affinity for conventional opiate receptors. σ sites display reverse stereoselectivity to classical opiate receptors. Multi-ringed opiate-related compounds such as morphine and naloxone have negligible affinity for σ sites, with the highest σ receptor affinity apparent for benzomorphans which lack the C ring of opioids. Highest affinity among opioids and other compounds occurs with more lipophilic N-substituents. This feature is particularly striking among the 3-PPP derivatives as well as the opioids. The butyrophenone haloperidol is the most potent drug at σ receptors we have detected. Among the series of butyrophenones, receptor affinity is primarily associated with the 4-phenylpiperidine moiety. Conformational calculations for various compounds indicate a fairly wide range of tolerance for distance between the aromatic ring and the amine nitrogen, which may account for the potency at σ receptors of structures of considerable diversity. Among the wide range of structures that bind to σ receptor-binding sites, the common pharmacophore associated with high receptor affinity is a phenylpiperidine with a lipophilic N-substituent.

Original languageEnglish (US)
Pages (from-to)772-784
Number of pages13
JournalMolecular Pharmacology
Volume32
Issue number6
StatePublished - 1987

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Opioid Analgesics
Butyrophenones
Opioid Receptors
Opiate Alkaloids
Benzomorphans
Binding Sites
Drug Receptors
Haloperidol
Naloxone
Morphine
Antipsychotic Agents
Amines
Nitrogen
preclamol

ASJC Scopus subject areas

  • Pharmacology

Cite this

Largent, B. L., Wikstrom, H., Gundlach, A. L., & Snyder, S. H. (1987). Structural determinants of σ receptor affinity. Molecular Pharmacology, 32(6), 772-784.

Structural determinants of σ receptor affinity. / Largent, B. L.; Wikstrom, H.; Gundlach, A. L.; Snyder, Solomon H.

In: Molecular Pharmacology, Vol. 32, No. 6, 1987, p. 772-784.

Research output: Contribution to journalArticle

Largent, BL, Wikstrom, H, Gundlach, AL & Snyder, SH 1987, 'Structural determinants of σ receptor affinity', Molecular Pharmacology, vol. 32, no. 6, pp. 772-784.
Largent BL, Wikstrom H, Gundlach AL, Snyder SH. Structural determinants of σ receptor affinity. Molecular Pharmacology. 1987;32(6):772-784.
Largent, B. L. ; Wikstrom, H. ; Gundlach, A. L. ; Snyder, Solomon H. / Structural determinants of σ receptor affinity. In: Molecular Pharmacology. 1987 ; Vol. 32, No. 6. pp. 772-784.
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