ncorporation of water-soluble address regions to the mu-selective agonist DAMGO resulted in enhanced BBB transport via membrane hopping without influencing the mu-selectivity and potency of the resulting glycopeptides. BBB penetration and analgesic potency increased with the size of the address region up to a maximum and then decreased as the molecule became more water soluble (i.e. demonstrated biousian behavior). Amphipathicities of the glycopeptide drugs were determined by calculating analytical Connolly surfaces using the molecular mechanics portion of the MOEŽ software package, and the amphipathicities were correlated to A(50) values determined using the tail flick assay in mice. Several of the resulting DAMGO glycopeptides show analgesic potencies far superior to morphine and seem to be viable pharmaceutical candidates. Support: Grants N00014-02-1-0471 & N00014-05-1-0807 from the Office of Naval Research and CHE-607917 from the National Science Foundation.