The discovery of CP-161,242 (5-cyano-l-[3-(N-methylpyrrolidin-2R-ylmethyl)indol-5-yl]benzimidazole), a potent, selective, orally active central serotonin (5-HT1D) agonist [IC50 (binding) = 1.3 nM, EC50 (inhibition of adenylate cyclase) = 42 pM] and benzodiazepine ligand [ICs0 (binding) = 3.3 riM], is presented.The large family of serotonin [5-hydroxytryptamine, 5-HT] receptors provides a plethora of medicinally important targets, and the neurotransmitter serotonin has been implicated in a wide variety of disease states ranging from depression and anxiety to migraine and sexual dysfunction. 2 The search for agents which are effective at only a single subtype within the large 5-HT receptor family should lead to new tools for understanding the function of the individual receptors and, possibly, new medicinal agents. From the clinical utility of Buspar®, a selective agonist at somatodendritic and postsynaptic 5-HTIA receptors, the anxiolytic activity associated with this receptor subtype has been demonstrated. 3 Even more recently, sumatriptan [Imigran®, 2 in Figure 1, where R5= -CH2SO2NHCH3], a 5-HT,,1.1ike,. agonist has been approved as a novel treatment for migraine headaches, and its selectivity for the 5-HT1D receptor has been proposed as the source of its anti-migraine activity. 4 The success of sumatriptan has initiated the search for other 5-HTID receptor selec-tive agonists with the purpose of further clarifying the mechanism of action of these compounds in relation to their anti-migraine activity. 5 Furthermore, since sumatriptan does not readily cross the blood/brain barrier, the role and function of 5-HT1D receptors within the mammalian central nervous system has not yet been elucidated.During the course of our studies in the area of conformationally restricted agonists of serotonin, 6 we discovered that the 3-(pyrrolidin-2R-ylmethyl) group in I was a novel, potent, and stereogenic replacement for the 3-(2-aminoethyl) group of serotonin and other tryptamines (2, Figure 1).6g , 6h At the same time, we also found a novel C5 substituent [Figure 1, 1 and 2, R5 = 5-(3-nitropyrid-2-ylamino)] on the indole nucleus which imparted reasonable selectivity for the 5-HT1D receptor. 6k Further SAR studies exploring this functionality led to 1-[3-(2-dimethylaminoethyl)indol-5-yl]pyrido[2,3-b]imidazole (4, Scheme 1). Compound 4 possessed improved 5-HT1D receptor selectivity when compared to the 5-(3-nitropyrid-2ylamino)tryptamine 6k (5). Therefore, the combination of our potent C3 substituent with a modified C5-pyrido[2,3-b]imidazole led to the discovery of 5-cyano-l-[3-(N-methylpyrrolidin-2R-ylmethyl)indol-5-yl]benzimidazole (3, CP-161,242, Figure 1). CP-161,242 was found to be a potent, orally active, 5-HT1D receptor selective agonist. During the course of general receptor binding studies with CP-161,242, it was discovered that the compound also possessed remarkable affinity for the benzodiazepine receptor as measured by displacement of [3H]flunitrazepam binding. This combination of potent and selective serotonergic agonism for the 5-HT1D receptor, coupled with its high affinity for the benzodiazepine receptor made CP-161,242 a unique pharmacological agent. In this report we detail the discovery and pharmacology of 5-cyano-l-[3-(N-methylpyrrolidin-2R-ylmethyl)indol-5 yl]benzimidazole (3, CP-161,242).