DOI AND ALPHA-METHYLSEROTONIN - COMPARATIVE VASCULAR AND NONVASCULAR SMOOTH-MUSCLE EFFECTS AND CENTRAL 5-HYDROXYTRYPTAMINE(2) RECEPTOR AFFINITIES

Both alpha-methylserotonin and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminop ropane (DOI) are agonists at 5-hydroxytryptamine2 (5-HT2) receptors. T he present study compared these agonists for their binding affinities at the high- and low-affinity states of the 5-HT2 receptor and for the ir contractile activities in certain smooth muscle preparations. Both agonists contracted the rat aorta and rat jugular vein, tissues posses sing 5-HT2 receptors, and contraction was blocked by ketanserin. Howev er, alpha-methylserotonin produced greater maximal response (80-90% ma ximum response to serotonin) than DOI. In the rat jugular vein, the ca lculated dissociation constant of DOI (-log K(b) = 7.7) corresponded w ell with its affinity for [H-3]ketanserin- (pK(i) = 7.5) but not [I-12 5]DOI- (pK(i) = 8.6) radiolabeled sites. This might suggest that bindi ng to the agonist low-affinity state of the 5-HT2 receptor is more rel evant to vascular agonist activity. Alpha-methylserotonin was slightly more potent than serotonin in contracting the rat aorta but not the j ugular vein, whereas DOI was more potent in the jugular vein than in t he aorta. In the jugular vein but not the aorta, the relative potency of these agents corresponded well with their relative affinities for e ither the [H-3]ketanserin- or the [I-125]DOI-labeled 5-HT2 receptor. T he lower contractile potency of DOI at 5-HT2 receptors in the aorta re lative to the jugular vein cannot be explained by: 1) tachyphylaxis to DOI in the aorta (single and cumulative concentrations of DOI gave si milar responses in the aorta), 2) a decreased number of 5-HT2 receptor s in the aorta (because alpha-methylserotonin was more potent than ser otonin) or 3) impaired receptor-effector coupling in the aorta (again, a-methylserotonin was more potent than serotonin). This dichotomy may reflect structural differences in the 5-HT2 receptor between the rat aorta and jugular vein. With regard to specificity, alpha-methylseroto nin was more potent than DOI in contracting non-5-HT2 receptor-mediate d tissues suggesting that alpha-methylserotonin has minimal 5-HT2 rece ptor selectivity relative to DOI. Thus, alpha-methylserotonin is a mor e efficacious agonist at 5-HT2 receptors than DOI, but lacks 5-HT2 rec eptor selectivity relative to DOI. Moreover, use of these agents adds further support to the presence of vascular 5-HT2 receptor heterogenei ty and to the functional importance of the low-affinity state of the 5 -HT2 receptor.