Putative sigma(3) sites in mammalian brain have histamine H(1) receptor properties: evidence from ligand binding and distribution studies with the novel H(1) radioligand [(3)H]-(-)-trans-1-phenyl-3-aminotetralin.
A novel phenylaminotetralin (PAT) radioligand, [(3)H]-(1R, 3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene ([(3)H]-[-]-trans-H(2)-PAT), is shown here to label a saturable (B(max)=39+/-6 fmol/mg protein) population of sites with high affinity (K(d)=0.13+/-0.03 nM) in guinea pig brain. Consistent with previous studies which showed that PATs stimulate catecholamine (dopamine) synthesis in rat striatum, autoradiographic brain receptor mapping studies here indicate that [(3)H]-(-)-trans-H(2)-PAT-labeled sites are highly localized in catecholaminergic nerve terminal fields in hippocampus, nucleus accumbens, and striatum in guinea pig brain. Competition binding studies with a broad range of CNS receptor-active ligands and CNS radioreceptor screening assays indicate that the pharmacological binding profile of brain [(3)H]-(-)-trans-H(2)-PAT sites closely resembles histamine H(1)-type receptors. Comparative studies using the histamine H(1) antagonist radioligand, [(3)H]mepyramine, indicate that the H(1) ligand binding profile and guinea pig brain distribution of H(1) receptors and [(3)H]-(-)-trans-H(2)-PAT sites are nearly identical; moreover, both sites have about 40-fold stereoselective affinity for (-)- over (+)-trans-H(2)-PAT. These results are discussed in light of previous studies which suggested that PATs stimulate dopamine synthesis through interaction with a novel sigma-type (sigma(3)) receptor in rodent brain; it now appears instead that PATs represent a new class of ligands for brain histamine H(1) receptors that can be stereoselectively labeled with [(3)H]-(-)-trans-H(2)-PAT.
Booth
R G
RG
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. rbooth@email.unc.edu
Owens
C E
CE
Brown
R L
RL
Bucholtz
E C
EC
Lawler
C P
CP
Wyrick
S D
SD
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D011738:Pyrilamine / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics*; D014316:Tritium
D011969:Receptors, Histamine H1; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes; D014316:Tritium; C084981:1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene; D011738:Pyrilamine