Structural determinants of sigma receptor affinity

Journal Article · Tue Dec 01 00:00:00 EST 1987 · Mol. Pharmacol.; (United States)

OSTI ID:5481466

Largent, B L; Wikstroem, H G; Gundlach, A L; Snyder, S H

The structural determinants of sigma receptor affinity have been evaluated by examining a wide range of compounds related to opioids, neuroleptics, and phenylpiperidine dopaminergic structures for affinity at sigma receptor-binding sites labeled with (+)-(/sup 3/H)3-PPP. Among opioid compounds, requirements for sigma receptor affinity differ strikingly from the determinants of affinity for conventional opiate receptors. Sigma sites display reverse stereoselectivity to classical opiate receptors. Multi-ringed opiate-related compounds such as morphine and naloxone have negligible affinity for sigma sites, with the highest sigma 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 sigma 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 distances between the aromatic ring and the amine nitrogen, which may account for the potency at sigma receptors of structures of considerable diversity. Among the wide range of structures that bind to sigma receptor-binding sites, the common pharmacophore associated with high receptor affinity is a phenylpiperidine with a lipophilic N-substituent.

• Research Organization: Johns Hopkins Univ., Baltimore, MD
• OSTI ID: 5481466
• Journal Information: Mol. Pharmacol.; (United States), Vol. 32:6
• Country of Publication: United States
• Language: English

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ENDORPHINS
RECEPTORS
AFFINITY
STRUCTURE-ACTIVITY RELATIONSHIPS
BIOCHEMICAL REACTION KINETICS
BRAIN
NARCOTICS
PHENOTHIAZINES
PIPERIDINES
RATS
TRACER TECHNIQUES
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AMINES
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DRUGS
HETEROCYCLIC COMPOUNDS
ISOTOPE APPLICATIONS
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MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
NEUROREGULATORS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
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PROTEINS
PYRIDINES
REACTION KINETICS
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550201* - Biochemistry- Tracer Techniques