Synthesis, molecular modeling, and dopamine receptor affinity of tetrahydroisoquinoline derivatives

Thesis/Dissertation · Fri Jan 01 04:00:00 EST 1988

OSTI ID:7266868

Charifson, P S

A series of 1-phenyl, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines have been prepared as ring contracted analogs of the prototypical D{sub 1} dopamine receptor antagonist, SCH23390 ((R+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). Two 4-phenyl-1,2,3,4-tetrahydroisoquinolines not prepared by the author were also evaluated. The affinity and selectivity of these tetrahydroisoquinolines for D{sub 1} receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to compete for ({sup 3}H)-SCH23390 binding sites; the potency to compete for ({sup 3}H)-spiperone binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D{sub 1} sites showed SCH23390 to possess the highest affinity, followed in order of decreasing potency by the 1-phenyl, 1-benzyl, and 4-phenylisoquinolines. Conformational studies on these tetrahydroisoquinolines using molecular mechanics (MM2-85), single crystal X-ray analysis and high-field NMR on both the free-base and ammonium forms of each compounds were carried out.

• Research Organization: North Carolina Univ., Chapel Hill, NC (USA)
• OSTI ID: 7266868
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
AFFINITY
AMINES
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
AZAARENES
AZINES
BODY
BRAIN
CARDIOTONICS
CARDIOVASCULAR AGENTS
CELL CONSTITUENTS
CELL MEMBRANES
CENTRAL NERVOUS SYSTEM
CHEMICAL PREPARATION
CPB
CYCLASES
DOPAMINE
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
LYASES
MAMMALS
MEMBRANE PROTEINS
MEMBRANES
MOLECULAR STRUCTURE
NERVOUS SYSTEM
NEUROREGULATORS
NMR SPECTRA
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PHENOLS
POLYPHENOLS
PROTEINS
PYRIDINES
QUINOLINES
RATS
RECEPTORS
RODENTS
SPECTRA
SYMPATHOMIMETICS
SYNTHESIS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES