Serotonin (5-HT) receptors have been classified in at least six subtypes, including 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT2, and 5-HT3. Part of our investigation on conformationally restricted analogues of serotonergic mediators was to identify a novel structural class of selective 5-HT1D receptor agonists as potential drugs for the treatment of migraine. We chose 5-carboxamidotryptamine (5-CT) as our starting compound because replacement of the hydroxy group in 5-HT with the amide in 5-CT has reportedly given good selectivity for the 5-HT1A and 5-HT1D receptor subtypes. While there have been investigations into the binding orientation of the ethylamino side chain of 5-HT at the 5-HT1A receptor (concluding a "northerly" orientation A), there have been no investigations into the likely binding conformation of either 5-HT or 5-CT at the 5-HT1D receptor. To investigate this, we prepared a number of conformationally-restricted analogues of 5-CT, including the 3-aminotetrahydrocarbazole 4 (BRL 56905) with an "easterly" orientation B of the side chain. 4 was synthesized via Fischer indole synthesis starting from 4-aminocyclohexanol (5) through N-protection, oxidation, cyclization, deprotection, N-reprotection, nitrile-to-amide conversion, and deprotection steps, with an overall yield of 45% from ketone 6. Binding affinity studies showed that 4 retained high 5-HT1D affinity equivalent to that of 5-HT, while its affinity at the 5-HT1A receptor was about 1000-fold lower than that of 5-CT, resulting in ~50-fold selectivity for the 5-HT1D receptor. 5-HT1C affinity of 4 was also much lower than that of 5-CT. Functional properties of 4 were investigated in two in vitro models (dog isolated saphenous vein and rabbit isolated basilar artery), where 4 was found to be a partial agonist with potency equal to or marginally greater than 5-HT and 5-8 times more potent than sumatriptan (8). In conclusion, conformational restriction of the ethylamino side chain of 5-CT in orientation B to form 4 resulted in a potent and selective 5-HT1D receptor partial agonist with intrinsic activity comparable to 8 but greater potency. This suggests that the binding orientation of the side chain of 5-CT at the 5-HT1D receptor may be orientation B.