To distinguish vasoactive intestinal peptide (VIP) receptors in the brain-mediating neurotransmission and neurotrophism, potent VIP analogues were designed. Using a single amino acid substitution and the addition of a fatty acyl moiety, an analogue was devised that exhibited both a 100-fold greater potency than VIP and specificity for a VIP receptor associated with neuronal survival. This VIP agonist increased neuronal survival via a cAMP-independent mechanism. Identical chemical modification of a prototype VIP antagonist (Met-Hybrid, Neurotensin6-11-VIP7-28) also resulted in a 100-fold greater potency in blocking VIP-mediated increases in neuronal survival. Blockade of circadian activity rhythms was limited to VIP antagonists that could inhibit VIP-mediated increases in cAMP. These lipophilic peptides provide novel tools in receptor discrimination and drug design.