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A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.

The pharmacological profile of WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino [6,7,1hi]indole], a novel 5-hydroxytryptamine (HT) 2C (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [125 I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT 2C receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K i value of 10.5 Ϯ 1.1 nM. Binding affinities determined for the human 5-HT 2A and 5-HT 2B receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT 2C receptor with an EC 50 value of 8 nM, and E max relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT 2A receptor subtype (EC 50 Ͼ Ͼ 10 M) and was a 5-HT 2B receptor partial agonist (EC 50 185 nM, E max 40%). WAY-163909 exhibited negligible affinity (Ͻ50% inhibition at 1 M) for other receptor sites examined, including human 5-HT 1A , D2, and D3 receptors, and the 5-HT transporter binding site in rat cortical membranes. WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT 7 (343 nM) receptor subtypes and the ␣1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED 50 ϭ 2.93 mg/kg), an effect blocked by a 5-HT 2C receptor antagonist but not by a 5-HT 2A or 5-HT 2B receptor antagonist. In addition, WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED 50 values of 1.4 and 5.19 mg/kg i.p., respectively, consistent with the potential utility of 5-HT 2C receptor agonists as antiobesity agents.At least 14 distinct 5-HT receptor subtypes have been cloned, and their classification has been based on both sequence similarity and common signal transduction pathways (for review, see Barnes and Sharp, 1999). The 5-HT 2 receptor subfamily currently accommodates three subtypes designated 5-HT 2A , 5-HT 2B , and 5-HT 2C , and these receptors belong to the large family of seven transmembrane domain G protein-coupled receptors. They display high sequence homology with each other and common signal transduction (Baxter et al., 1995), principally via the activation of phospholipase C. Alterations or dysfunction of the 5-HT 2C receptor has been implicated in a variety of conditions, including obesity, anxiety, depression, obsessive compulsive disorder, schizophrenia, migraine, and erectile dysfunction (Fozard and Gray, 1989;Kennett and Curzon, 1991;Sanders-Bush Article, publication date, and citation information can be found at

5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.

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