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Abstract S 20499 is the (+) enantiomer of the racemic compound S 20244 (4‐N‐(methoxychromane‐3‐yl) N‐propylamino butyl‐8‐azaspiro 4,5 decane‐7,9 dione), a novel 5‐hydroxytryptamine 1A (5‐HT 1A ) agonist. The present experiments examined the potential anxiolytic and 5‐HT 1A agonist activity of S 20499 (+) in behavioral experiments in rodents. Tests used were the lrwin, activity meter, and tail suspension tests in mice and the Vogel conflict, forepaw treading, and lower lip retraction tests in rats. Further tests examined its duration of activity and the effects of chronic treatment. In most experiments, its effects were compared with the (−) enantiomer (S 20500). Neither S 20499 (+) nor S 20500 (−) was lethal in mice up to 256 mg/kg. S 20499 (+) induced signs of sedation (hypoactivity, decreased traction and muscle tone, ptosis, and hypothermia) in the lrwin test in the dose range 4–64 mg/kg i.p. and a dose‐dependent decrease in locomotion (activity meter) from 2 mg/kg. At high doses (128–256 mg/kg) S 20500 (−) had qualitatively different effects, inducing signs of excitation and stereotyped behavior. At lower doses (16–64 mg/kg), its effects were similar to those of S 20499 (+) but it was between two‐ and fourfold less potent. S 20499 (+) increased the duration of immobility in the tail suspension test (anxiolytic/tranquilizing activity) from 16 mg/kg, whereas S 20500 (−) had no effects up to 32 mg/kg. BothS 20499 (+) and S 20500 (−) increased the number of shocks taken in the Vogel conflict test (anxiolytic activity) at 4 and 16 mgikg, respectively. The duration of activity of S 20499 (+) was between 2 and 4 hr and its effects were maintained after chronic administration over 5 days. Finally, both enantiomers induced forepaw treading and lower lip retraction in rats (signs of 5‐HT, agonist activity), with S 20499 (+) being at least four times as potent as S 20500 (−). Taken together, the results are consistent with other available data suggesting potential anxiolytic activity for S 20499 (+), probably arising through its agonist activity at central 5‐HT 1A , receptors. © 1992 Wiley‐Liss, Inc.