N(1)-SUBSTITUTED ERGOLINES AND TRYPTAMINES SHOW SPECIES-DIFFERENCES FOR THE AGONIST-LABELED 5-HT(2) RECEPTOR

Previous studies indicated that selected ergolines and tryptamines sho wed species differences for affinity to the antagonist-labeled 5-HT2 r eceptor. The present study examined these same compounds for affinity at the agonist-labeled 5-HT2 receptor in rat and squirrel monkey corti cal homogenates using [I-125]DOI 25]1-(2,5-dimethoxy-4-iodophenyl)-2-a minopropane). As seen with the antagonist-labeled 5-HT2 receptor, N(1) alkLyl substitution of either the ergolines or tryptamines resulted i n a slight increase or no effect on their affinity for the agonist-lab eled rat 5-HT2 receptor. In contrast, these same N(1) substitutions re sulted in significant decreases in affinity for the agonist-labeled mo nkey 5-HT2 receptor. It was also noted that N(1)-unsubstituted ergolin es and tryptamines (such as ergonovine, LY86057, LY193525 and 5-methox ytryptamine) tended to have higher affinity for the monkey versus the rat agonist-labeled receptor. However, the N(1) alkyl-substituted ergo lines and tryptamines (such as mesulergine, LY53857, amesergide, N(1)- isopropyltryptamine and N(1)-isopropyl-5-methoxytryptamine) showed sig nificantly lower affinity for the monkey versus the rat 5-HT2 receptor . These data suggest that, at least in relation to the N(1) position, ergolines and tryptamines bind in a similar orientation. These results are also discussed in terms of what amino acid differences between sp ecies may account for this structure-activity relationship.