Neurotrophic peptides incorporating adamantane improve learning and memory, promote neurogenesis and synaptic plasticity in mice
Li B, Wanka L, Blanchard J, Liu F, Chohan MO, Iqbal K, Grundke-Iqbal I. FEBS Lett. 2010 Aug 4;584(15):3359–3365. doi:10.1016/j.febslet.2010.06.025 View source ↗
This study introduced two adamantane-modified hexapeptide derivatives — P21 (Ac-DGGLAG-NH2 with C-terminal 3-aminoadamantane-1-carboxylic acid) and P22 (1-Ad-CO-DGGLAG-NH2, in which an adamantanecarbonyl group replaces the smaller N-acetyl group at the N-terminus). The compounds were administered peripherally to adult mice and evaluated in the Morris water maze, novel object recognition, and histological assessments of hippocampal neurogenesis and synaptic protein expression. P21 produced statistically significant improvements across multiple endpoints, including spatial learning probe trials, object recognition preference, increased hippocampal progenitor proliferation, and elevated synaptophysin and synapsin I expression. P22, in contrast, did not reach statistical significance on probe-trial spatial memory or on the novel-object preference index. The authors suggested that the bulky N-terminal adamantane moiety in P22 likely interfered with proper interaction of the active DGGL subsequence with its biological target, and presented P22 primarily as a structure-activity counterexample establishing the importance of the smaller N-acetyl group in P21. To our knowledge, P22 has not been the primary subject of a subsequent independent in vivo study indexed in the Western peer-reviewed literature.
Researchers built two related peptides, P21 and P22, that share the same six-amino-acid core but differ in what is attached to one end. P21 worked: mice given P21 learned faster on a swimming maze, paid more attention to new objects, grew more new brain cells in the hippocampus, and showed increases in proteins associated with the connections between brain cells. P22, on the other hand, did not produce a statistically significant improvement on the harder memory tests, and the authors concluded that the larger chemical group on P22's end probably got in the way of the molecule fitting its target. In other words, in the only published comparison of the two, P22 was the negative control that helped explain why P21 works. Researchers should weigh this carefully: P22's published record is small, and the headline result for it is "did not work as well as P21" rather than positive findings of its own.
