Pharmacological blockade of central H3Rs with ciproxifan, thioperamide and GT-2331 enhances attention and cognition in rodents. However, these compounds share the imidazole moiety with the endogenous agonist, histamine, and have high affinity for several additional receptors. Here, we present in vivo behavioral data for 2 novel and selective, non-imidazole H3R antagonists with improved safety indices (for in vitro data, see accompanying poster by Yao et al., SFN 2002). A-304121 and A-317920, 2 novel piperazine amides, were tested in a 5-trial, repeated acquisition, inhibitory avoidance test in the rat pup. Significantly improved performance was observed following administration of A-304121 (10 mg/kg sc) or A-317920 (3 mg/kg sc), with efficacy comparable to reference H3R blockers thioperamide (10 mg/kg sc), ciproxifan (3 mg/kg sc), and GT-2331 (1 mg/kg sc). Relative therapeutic indices (TIs) of 30 and 42 were estimated for A-304121 and A-317920, respectively, from observation of CNS adverse effects in mouse...