1,3-Di(2-(5-/sup 3/H)tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs

Journal Article · Fri Oct 31 23:00:00 EST 1986 · Proc. Natl. Acad. Sci. U.S.A.; (United States)

DOI:https://doi.org/10.1073/pnas.83.22.8784· OSTI ID:6963831

Weber, E; Sonders, M; Quarum, M; McLean, S; Pou, S; Keana, J F

Brain sigma-type receptors are thought to mediate hallucinogenic effects of certain benzomorphan opiates in humans. The biochemical characterization of sigma receptors has been difficult because of the lack of potent and selective ligands. We report here the synthesis and characterization of a tritiated, symmetrically substituted guanidine derivative, 1,3-di(2-(5-/sup 3/H)tolyl)guanidine ((/sup 3/H)Tol2Gdn), that binds with high affinity to a single population of binding sites in guinea pig brain membrane preparations. The (/sup 3/H)Tol2Gdn binding site displays stereoselectivity for dextrorotatory optical isomers of benzomorphan opiates known to have sigma-type behavioral effects. Furthermore, the (/sup 3/H)Tol2Gdn binding site has a high affinity for haloperidol and for phenothiazine antipsychotics, which have antihallucinatory properties in humans. The drug-selectivity profile of (/sup 3/H)Tol2Gdn binding closely correlates with the drug-selectivity profile of tritiated (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (+)-(/sup 3/H)3-PPP) binding to guinea pig brain membrane receptors. (+)-(/sup 3/H)3-PPP has been proposed to be a selective sigma-receptor ligand (Largent, B. L., Gundlach, A. L. and Snyder, S. H. (1984) Proc. Natl. Acad. Sci. USA 82, 4983-4987). Receptor autoradiography using (/sup 3/H)Tol2Gdn on slide-mounted rat and guinea pig brain sections reveals a heterogeneous distribution pattern of enriched binding in limbic and sensorimotor structures of the brain. These results indicate that (/sup 3/H)Tol2Gdn is a selective ligand for the sigma-site. Availability of this sigma-receptor probe should greatly facilitate the physiological, biochemical, and pharmacological characterization of sigma receptors in brain.

• Research Organization: Oregon Health Sciences Univ., Portland
• OSTI ID: 6963831
• Journal Information: Proc. Natl. Acad. Sci. U.S.A.; (United States), Journal Name: Proc. Natl. Acad. Sci. U.S.A.; (United States) Vol. 22; ISSN PNASA
• Country of Publication: United States
• Language: English

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551001* -- Physiological Systems-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AMINES
ANIMALS
AUTORADIOGRAPHY
AZINES
BODY
BRAIN
CARBONIC ACID DERIVATIVES
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM AGENTS
DRUGS
GUANIDINES
GUINEA PIGS
HALLUCINOGENS
HETEROCYCLIC COMPOUNDS
IN VITRO
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
LABELLING
LIGANDS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PIPERIDINES
PROTEINS
PSYCHOTROPIC DRUGS
PYRIDINES
RADIORECEPTOR ASSAY
RATS
RECEPTORS
RODENTS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES