PMID- 10089574
OWN - NLM
STAT- MEDLINE
DCOM- 19990423
LR  - 20151119
IS  - 0031-6768 (Print)
IS  - 0031-6768 (Linking)
VI  - 437
IP  - 4
DP  - 1999 Mar
TI  - Influence of substrate structure on substrate binding to the renal organic 
      cation/H+ exchanger.
PG  - 603-10
AB  - The carrier-mediated exchange of H+ for organic cations ("OC/H+ exchange") is the 
      active step in OC secretion in renal proximal tubules. Although hydrophobicity is 
      known to be an important criterion for binding of substrates to this transporter, 
      the degree to which steric parameters of substrate structure influence binding to 
      the exchanger is unclear. We examined this issue by measuring the inhibition of 
      OC/H+ exchange produced by a group of quaternary ammonium compounds which share a 
      common structural motif: an N1-pyridinium residue. Activity of the OC/H+ 
      exchanger was determined by measuring transport of [14C]tetraethylammonium (TEA) 
      in brush-border membrane vesicles (BBMV) from rabbit renal cortex. Transport was 
      measured in the presence of a pH gradient (pHin 6.0; pHout 7.5) to maximize 
      TEA/H+ exchange. Apparent inhibitory constants (Ki values) for each test agent 
      were measured. The test agents included 4-phenylpyridiniums and 
      3-phenylpyridiniums, quinoliniums and acridiniums. The planar structure of these 
      compounds permits a direct test of whether the presence of planar hydrophobic 
      mass in different orientations relative to the pyridinium motif exerts a 
      systematic effect on substrate binding to the OC/H+ exchanger. The hydrophobicity 
      of each group of compounds was systematically varied by addition of different 
      substituents at the quaternary nitrogen. Whereas decreases in Ki proved to be 
      proportional to hydrophobicity, the position of the phenyl-ring substituent(s) 
      had no effect on substrate interaction with the exchanger. The results led to the 
      development of a preliminary quantitative structure-activity relationship (QSAR) 
      correlating substrate hydrophobicity and substrate binding to the OC/H+ 
      exchanger. This QSAR was used to predict the binding of 
      1-methyl-4-phenylpyridinium (MPP+), (+) and (-)nicotine, (+) and (-)ephedrine, 
      quinine and quinidine to the OC/H+ exchanger. Molecular graphics representation 
      of the 3D structures of the test agents was used to develop a working model of a 
      hydrophobic, planar receptor surface on the OC/H+ exchanger against which 
      substrates are suggested to interact during binding. Development of the QSAR and 
      receptor surface model open the way to quantitative tests of the specific 
      physical and structural determinants of substrate selectivity by the renal OC/H+ 
      exchanger.
FAU - Wright, S H
AU  - Wright SH
AD  - Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ 
      85724, USA. shwright@u.arizona.edu
FAU - Wunz, T M
AU  - Wunz TM
LA  - eng
GR  - DK49222/DK/NIDDK NIH HHS/United States
GR  - ES06694/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - Germany
TA  - Pflugers Arch
JT  - Pflugers Archiv : European journal of physiology
JID - 0154720
RN  - 0 (Acridines)
RN  - 0 (Antiporters)
RN  - 0 (Carbon Radioisotopes)
RN  - 0 (Cations)
RN  - 0 (Pyridinium Compounds)
RN  - 0 (Quinolinium Compounds)
RN  - 66-40-0 (Tetraethylammonium)
RN  - 6M3C89ZY6R (Nicotine)
RN  - A7V27PHC7A (Quinine)
RN  - GN83C131XS (Ephedrine)
RN  - ITX08688JL (Quinidine)
SB  - IM
MH  - Acridines/chemistry/metabolism
MH  - Animals
MH  - Antiporters/*metabolism
MH  - Carbon Radioisotopes
MH  - *Cations
MH  - Ephedrine/chemistry/metabolism
MH  - Ion Transport
MH  - Kidney Cortex/*chemistry
MH  - Microvilli/metabolism
MH  - Molecular Structure
MH  - Nicotine/chemistry/metabolism
MH  - Pyridinium Compounds/chemistry/metabolism
MH  - Quinidine/chemistry/metabolism
MH  - Quinine/chemistry/metabolism
MH  - Quinolinium Compounds/chemistry/metabolism
MH  - Rabbits
MH  - Stereoisomerism
MH  - Structure-Activity Relationship
MH  - Tetraethylammonium/*metabolism
EDAT- 1999/03/25 00:00
MHDA- 1999/03/25 00:01
CRDT- 1999/03/25 00:00
PHST- 1999/03/25 00:00 [pubmed]
PHST- 1999/03/25 00:01 [medline]
PHST- 1999/03/25 00:00 [entrez]
AID - 10.1007/s004240050823 [pii]
AID - 10.1007/s004240050823 [doi]
PST - ppublish
SO  - Pflugers Arch. 1999 Mar;437(4):603-10. doi: 10.1007/s004240050823.