Binding properties of aminophenyl carboxamide derivatives of the alpha/sub 2/-adrenergic receptor antagonists, rauwolscine and yohimbine: spatial and stereochemical considerations

Conference · Thu May 01 00:00:00 EDT 1986 · Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States)

OSTI ID:5151341

Lanier, S M; Hess, H J; Grodsky, A; Homcy, C J; Graham, R M

The authors have recently characterized the radioiodinated analog of a carboxamide derivative of rauwolscine (RAU) (17 ..cap alpha..-hydroxy-20..cap alpha..-yohimban-16..beta..-(N-4-aminophenethyl)carboxamide) as a high-affinity probe for ..cap alpha../sub 2/-adrenergic receptors (..cap alpha../sub 2/-R). To investigate the spatial requirements of the receptor's ligand-binding site, the authors have synthesized carboxamide derivatives of RAU in which the aminophenyl group is separated from the parent compound by 0 (I), 2 (II) or 4 (III) atoms. In competition studies with /sup 3/H-RAU utilizing rat kidney membranes, I, RAU, II and III exhibited K/sub i/'s of 1.9 +/- 0.1, 4.7 +/- 0.2, 13 +/- 0.5 and 16 +/- 0.7 nM, respectively. The stereochemical requirements of the receptor's ligand binding site were also studied following the synthesis of similar carboxamide derivatives of yohimbine (YOH), a diastereoisomer of rauwolscine. In contrast to the high affinity observed with I and II, the corresponding derivatives of YOH exhibited 15 to 100-fold lower affinity. Iodination of I yields a radioligand (2175Ci/mmol) of high-affinity (K/sub D/ = 600pM) at the renal ..cap alpha../sub 2/-R and this compound should prove useful in biochemical studies of this ..cap alpha..-adrenergic receptor subtype. These data indicate that the spatial orientation of the aminophenyl substituent is an important determinant of high-affinity binding at ..cap alpha../sub 2/-R.

• Research Organization: Massachusetts General Hospital, Boston
• OSTI ID: 5151341
• Report Number(s): CONF-8606151-
• Journal Information: Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 45:6; Conference: 76. annual meeting of the Federation of American Society for Experimental Biology, Washington, DC, USA, 8 Jun 1986
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
RECEPTORS
BIOCHEMICAL REACTION KINETICS
SYMPATHOMIMETICS
AFFINITY
CELL MEMBRANES
IODINE ISOTOPES
KIDNEYS
LIGANDS
RATS
STEREOCHEMISTRY
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
CELL CONSTITUENTS
DRUGS
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
MAMMALS
MEMBRANE PROTEINS
MEMBRANES
ORGANIC COMPOUNDS
ORGANS
PROTEINS
REACTION KINETICS
RODENTS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques