Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor

Journal Article · Wed May 01 00:00:00 EDT 1991 · Journal of Medicinal Chemistry; (USA)

DOI:https://doi.org/10.1021/jm00109a029· OSTI ID:5638979

Milius, R A; Saha, J K; Madras, B K; Neumeyer, J L ^[1]

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1. Research Biochemicals Inc., Natick, MA (USA)

The synthesis and pharmacological characterization of a series of N-substituted 3-(4-fluorophenyl)tropane derivatives is reported. The compounds displayed binding characteristics that paralleled those of cocaine, and several had substantially higher affinity at cocaine recognition sites. Conjugate addition of 4-fluorophenyl magnesium bromide to anhydroecgonine methyl ester gave 2 beta-(carbomethoxy)-3 beta-(4-fluorophenyl)tropane (4a, designated CFT, also known as WIN 35,428) after flash chromatography. N demethylation of 4a was effected by Zn/HOAc reduction of the corresponding 2,2,2-trichloroethyl carbamate to give 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)nortropane (5), which was alkylated with allyl bromide to afford the N-allyl analogue, 6. The N-propyl analogue, 7, was prepared by catalytic reduction (Pd/C) of 6. The most potent analogue, 4a, was tritiated at a specific activity of 81.3 Ci/mmol. ({sup 3}H)4a bound rapidly and reversibly to caudate putamen membranes; the two-component binding curve typical of cocaine analogues was observed. Equilibrium was achieved within 2 h and was stable for at least 4 h. High- and low-affinity Kd values observed for ({sup 3}H)4a (4.7 and 60 nM, respectively) were more than 4 times lower than those for ({sup 3}H)cocaine, and the density of binding sites (Bmax = 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding of ({sup 3}H)4a was 5-10% of total binding.

• OSTI ID: 5638979
• Journal Information: Journal of Medicinal Chemistry; (USA), Vol. 34:5; ISSN 0022-2623
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
COCAINE
RECEPTORS
LIGANDS
STRUCTURE-ACTIVITY RELATIONSHIPS
AFFINITY
BIOCHEMICAL REACTION KINETICS
PHARMACOLOGY
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ALKALOIDS
ANESTHETICS
ANTIDEPRESSANTS
CENTRAL NERVOUS SYSTEM AGENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DRUGS
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MEMBRANE PROTEINS
ORGANIC COMPOUNDS
PROTEINS
PSYCHOTROPIC DRUGS
REACTION KINETICS
550201* - Biochemistry- Tracer Techniques