Characterization of the enantiomers of cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)cyclohexylamine (BD737 and BD738): novel compounds with high affinity, selectivity and biological efficacy at sigma receptors

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 262; no. 1; pp. 32 - 40
• Main Authors: BOWEN, W. D, WALKER, J. M, DE COSTA, B. R, WU, R, TOLENTINO, P. J, R, FINN, D, ROTHMAN, R. B, RICE, K. C
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.07.1992
• Subjects: Analgesics - metabolism; Analgesics - pharmacology; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Cell Membrane - drug effects; Cyclohexylamines - metabolism; Cyclohexylamines - pharmacology; Guinea Pigs; Male; Medical sciences; Miscellaneous; Motor Activity - drug effects; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Phosphatidylinositols - metabolism; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Rats; Rats, Inbred Strains; Receptors, Opioid - metabolism; Receptors, sigma; Stereoisomerism; Synaptosomes - drug effects; Synaptosomes - metabolism; Rodentia; Central nervous system; Biomembrane; Selectivity; In vitro; Vertebrata; Biological fixation; Mammalia; Guinea pig; Animal; σ receptor; Affinity; Brain (vertebrata)
• ISSN: 0022-3565; 1521-0103

A novel class of compounds with very high affinity and selectivity for sigma receptors has been discovered. BD614 [(+/-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1- pyrrolidinyl)cyclohexylamine] and its optically pure 1S,2R-(-)-[BD737] and 1R,2S-(+)-[BD738]enantiomers bound to sigma receptors of guinea pig brain with Ki = 2.0 +/- 0.4, 1.3 +/- 0.3 and 6 +/- 3 nM, respectively. These compounds exhibited little or no affinity for dopamine-D2, kappa opiate or phencyclidine receptors and displayed high biological efficacy in assays of sigma receptor function, ability to produce alterations in motor behavior and inhibition of the muscarinic cholinergic phosphoinositide response. Microinjection of BD614 into the rat red nucleus or substantia nigra produced a dose-dependent alteration in head position and contralateral circling, respectively. BD614, BD737 and BD738 inhibited stimulation of inositol phosphate production by carbachol or oxotremorine-M in a dose-dependent manner. Thus, N-substituted cis-2-(1-pyrrolidinyl)cyclohexylamines may prove useful in studies of sigma receptor structure and function.