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 language | English (US) |
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Pages (from-to) | 772-784 |
Number of pages | 13 |
Journal | Molecular Pharmacology |
Volume | 32 |
Issue number | 6 |
State | Published - 1987 |
ASJC Scopus subject areas
- Molecular Medicine
- Pharmacology