Antihypertensive drugs that decrease total peripheral resistance can also reduce renal blood flow and urinary sodium excretion, leading to volume expansion and attenuation of the hypotensive effectiveness of the compound. In this paper, we describe a novel antihypertensive agent (1, MDL 19,744A), which selectively blocks α₁-adrenergic receptors and increases renal blood flow and sodium excretion in anesthetized dogs. The dose-dependent increases in renal blood flow were blocked by the dopamine receptor antagonists SCH 23390 and sulpiride, suggesting that this effect was mediated by activation of renal vascular dopamine (DA₁) receptors. Initial studies on the conformational requirements for adrenergic receptors and the observation that certain thiopheneamines act as α-adrenergic receptor blockers led to the synthesis of 1 and its stereoisomers 7-9 via a convergent synthetic route. Stereospecific synthetic routes have been developed for the three diastereomeric amines 7a-9a, and details of these compounds and corresponding derivatives will be reported subsequently. The hypotensive effects of the four stereoisomers (1, 7b, 8b, 9b) were examined in chronically cannulated spontaneously hypertensive rats (SHR) and anesthetized normotensive dogs; compound 1 was the most potent hypotensive agent in both species, and the stereochemical configuration of functional groups around the cyclopentyl ring was critical for activity. Interaction with α-adrenoreceptors was studied in vitro (isolated rabbit aortic strips, radioligand receptor binding) and in vivo (pithed rat); compound 1 was a potent, selective α₁ antagonist with weak α₂ antagonism and no β-adrenergic blocking activity. Renal effects of cumulative intravenous doses of 1 in anesthetized dogs included dose-related increases in renal blood flow and urinary sodium excretion (with unchanged glomerular filtration rate), which were blocked or attenuated by pretreatment with dopamine receptor antagonists, indicating mediation by DA₁ receptors. Compound 1 lacks significant DA₂ receptor activity (no emesis in dogs/monkeys) and is currently being evaluated for clinical effectiveness in the treatment of hypertension.