α- Adrenoceptors exist as two distinct subclasses that have been characterized both pharmacologically and functionally. The evidence for this classification has been recently al- and α2-adrenoceptors are generally distinguished by their selectivity toward a standard series of agonists and antagonists, irrespective of anatomical distribution. Recent work has also provided a biochemical and basis for differentiating these receptors. The physiological significance of α2-adrenoceptors is currently an area of considerable interest. Stimulation of prejunctional α2-adrenoceptors inhibits release of norepinephrine from noradrenergic nerve terminals and thereby modulates synaptic and circulating concentrations of this neurotransmitter. Postjunctional α2-adrenoceptors mediate contraction of vascular smooth muscle and regulate secretion of certain hormones. Stimulation of medullary α2-adrenoceptors by the α2-agonist clonidine results in reduced peripheral sympathetic tone and enhanced vagal tone. Consequently, both blood pressure and heart rate fall. Compounds that are selective agonists or antagonists for these receptor subtypes offer possibilities for developing novel therapeutic agents and also may serve as valuable tools for investigating the physiological roles of α-adrenoceptors. In this paper we describe the synthesis and characterization of a highly potent and selective α2-adrenoceptor antagonist, N-(1,3,4,6,7,12b-hexahydro-2H-benzo[b]furo[2,3-a]quinolizin-2-yl)-N-methyl-2-hydroxyethanesulfonamide, 6. We also report the stereoselective preference of α2-adrenoceptors for one enantiomer of this compound. In our attempt to ultimately design small molecules that act as vasopressin receptor antagonists, an initial goal has been to define the minimum active fragment of the class of peptide V2-receptor antagonists first described by Manning et al. (exemplified by compound 1, Figure 1). We have focused a portion of our effort on the tripeptide tail which is common to these antagonists as well as to vasopressin. This tail is postulated to contain key binding elements of the agonist pharmacophore. It has recently been shown by Manning et al. and independently by us that potent octapeptide vasopressin antagonists can be obtained by deletion of the carboxyl-terminal glycine moiety, leaving a carboxyl-terminal argininamide, for example compounds 2 (SK&F 101926) and 3. We have previously presented evidence that the pharmacophore requirements at the renal V2-receptor differ for vasopressin agonists and antagonists. For example, analogues of 1 (or its L-Tyr(Et)2 congener) with either D- or L-arginine at position 8 are essentially equipotent, which is not the case with agonists. This suggested that the terminal carboxamide group in 2 or 3 may not be essential in the antagonist pharmacophore since this situation would allow the D- and L-arginine analogues to be topochemically equivalent. This hypothesis was tested by the preparation of compound 4, in which the lysine of 3 is replaced by an alkyldiamine.