The endogenous opioid pentapeptides [Met5]enkephalin (H-TyrGly-Gly-Phe-Met-OH) and [Leu5]enkephalin (H-Tyr-Gly-GlyPhe-Leu-OH) have been shown to interact with several classes of opioid receptors (1-3) that may mediate different physiological responses. Elucidation of the roles of the individual receptor classes has been hampered by the general lack of enkephalin analogs with a high degree of selectivity for a single receptor type. The vast majority of analogs crossreact extensively with the different receptors, making it difficult to define receptor roles. This situation has been in part ameliorated by recent reports of an enkephalin analog highly selective for the ,At opioid receptor (4-6) and a nonpeptide opiate with high K receptor selectivity (7). However, analogs with corresponding selectivity for the 8 opioid receptor have not been demonstrated.One approach for the design of more selective analogs involves the incorporation of conformational restrictions. The native enkephalins, like most small, linear peptides, possess considerable conformational flexibility and by virtue of this flexibility can attain the presumably different conformational features required for interaction with different classes of opioid receptors. In principle, appropriate restriction of this flexibility can lead to analogs able to assume the conformation required to interact favorably with only one class of receptor. One method for effecting conformational restrictions is via cyclization of the peptide that constrains the resulting analog to assume a compact topography. Several active, cyclic enkephalin analogs have been reported, all of which are cyclized by either side chain to carboxyl terminus (8,9) It has previously been shown that, in aqueous solution, the tocin ring portion of Pen-containing oxytocin analogs is conformationally restricted, whereas the tocin ring of oxytocin itself is quite flexible (13-16). This difference arises from the rigidifying effect of gem-dialkyl substituents in medium-sized rings and suggests that the 8 (Fig. 1) The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Activation of brain ␣7 nicotinic acetylcholine receptors (␣7 nAChRs) has broad therapeutic potential in CNS diseases related to cognitive dysfunction, including Alzheimer's disease and schizophrenia. In contrast to direct agonist activation, positive allosteric modulation of ␣7 nAChRs would deliver the clinically validated benefits of allosterism to these indications. We have generated a selective ␣7 nAChR-positive allosteric modulator (PAM) from a library of GABA A receptor PAMs. Compound 6 (N-(4-chlorophenyl)-␣-[[(4-chlorophenyl)amino]methylene]-3-methyl-5-isoxazoleacet-amide) evokes robust positive modulation of agonist-induced currents at ␣7 nAChRs, while preserving the rapid native characteristics of desensitization, and has little to no efficacy at other ligand-gated ion channels. In rodent models, it corrects sensory-gating deficits and improves working memory, effects consistent with cognitive enhancement. Compound 6 represents a chemotype for allosteric activation of ␣7 nAChRs, with therapeutic potential in CNS diseases with cognitive dysfunction.cognition ͉ ion channels ͉ memory ͉ nicotine ͉ schizophrenia

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