Characterization of ligand binding properties of the 5-HT1D receptors cloned from chimpanzee, gorilla and rhesus monkey in comparison with those from the human and guinea pig receptors.
The 5-HT1D receptor is a potential target of anti-migraine drugs, and here its genes were cloned from chimpanzee, gorilla and rhesus monkey, via polymerase chain reactions with their genomic DNAs and the primers designed from the 5' and 3' untranslated regions of the human receptor. Direct sequencing of the polymerase chain reaction (PCR) products revealed high degrees of identity between their deduced amino acid sequences (the chimpanzee, gorilla and rhesus monkey) and that of human, differing by two, four and 11 residues, respectively. The binding properties of the receptors, as expressed in human embryonic kidney 293 cells, were compared to those obtained with the human and guinea pig receptors, the latter differing by 33 residues from the human receptor. Standard serotonergic ligands including several indoles, ergots and methiothepin bound all the cloned primate and guinea pig receptors with comparable, low nanomolar affinities, leading to high correlation coefficients among their Ki values. R(+)-8-Hydroxydipropylaminotetralin, on the other hand, bound the human receptor with the affinity higher than those for the primates and guinea pig receptors. This indicates that certain chemical templates may differentiate the molecular divergences among the 5-HT1D receptors of various animal species, and the use of the non-human primates will be beneficial for pharmacological characterizations, more relevant to the human receptor, of future novel ligands for the 5-HT1D receptor, which are potential anti-migraine drugs.
Pregenzer
J F
JF
CNS Diseases Research and Molecular Biology, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49001, USA.
Alberts
G L
GL
Bock
J H
JH
Slightom
J L
JL
Im
W B
WB
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D006071:Gorilla gorilla; D006168:Guinea Pigs / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008253:Macaca mulatta; D002679:Pan troglodytes; D011323:Primates / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D013045:Species Specificity
D008024:Ligands; D011985:Receptors, Serotonin