Species differences in the pharmacology of the 5-hydroxytryptamine2 receptor: structurally specific differentiation by ergolines and tryptamines.
Species differences in the recognition of a series of ergolines by the 5-hydroxytryptamine2 (5-HT2, serotonin2) receptor were investigated in four species, the rat, pig, squirrel monkey and human. In pig frontal cortical membranes the initial studies showed that the ergolines gave shallow displacement curves against [3H]ketanserin binding. The component of [3H]ketanserin binding having low affinity for the ergolines was determined to be the result of [3H]ketanserin binding to alpha-1 adrenergic receptors. Thus, in all subsequent assays prazosin was used to mask [3H]ketanserin binding to alpha-1 adrenergic receptors. Examination of a series of ergolines revealed a distinct pattern in the species selectivity. Compounds that were unsubstituted at the N1 position of the ergoline nucleus showed higher affinity for the pig, squirrel monkey and human 5-HT2 receptors than for the rat. Conversely, compounds that had an N1-isopropyl substituent showed higher affinity for the rat receptor compared to the pig, squirrel monkey and human 5-HT2 receptors. For example, LY53857, a widely used 5-HT2 antagonist, has an isopropyl substituent at position N1 of the ergoline nucleus and exhibited a 4- to 5-fold higher affinity for the rat 5-HT2 receptor, whereas its N1-unsubstituted homologue, LY86057, had more than 10-fold higher affinity for the pig, squirrel monkey and human 5-HT2 receptors. Similar results were seen with three additional ergoline pairs, each having different substituents at the C8 position compared to LY53857. Even an N1-substitution on LY53857 as small as a methyl group, LY108742, resulted in the compound having higher affinity for the rat 5-HT2 receptor compared to the other species.(ABSTRACT TRUNCATED AT 400 WORDS)
Nelson
D L
DL
CNS/GI/GU Division, Lilly Research Laboratories, Indianapolis, Indiana.
Lucaites
V L
VL
Audia
J E
JE
Nissen
J S
JS
Wainscott
D B
DB
D000818:Animals; D002478:Cells, Cultured; D004873:Ergolines / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D012453:Saimiri; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013552:Swine; D014363:Tryptamines / Q000737:chemistry / Q000378:metabolism*
D004873:Ergolines; D011985:Receptors, Serotonin; D014363:Tryptamines; D007650:Ketanserin