title: Relationships between structure and duration of neurotensin's central action: emergence of long acting analogs.
abstract: Relationships between structure and duration of neurotensin's central action were examined. Included in the study were analogs containing amino acid substitutions at purported enzymatic cleavage sites of neurotensin: the arg8-arg9, the Pro10-Tyr11, and the Tyr11-Ile12 peptide bonds. Peptides were administered in rats via the cerebro-ventricular route and the ensuing hypothermia was monitored repeatedly until the effect dissipated. Results indicate that substitutions of the Tyr11 residue of the neurotensin molecule with either Dopa, Trp, D-Trp, or D-Tyr yielded analogs displaying markedly increased durations of action. Substitutions at other sites did not alter the time course of neurotensin's hypothermic effect. The longest acting analog was [Dopa11]-NT. At a dose of 7.5 micrograms the hypothermia induced by this analog persisted for 660 min while the effect of a same dose of neurotensin endured for only 90 min after injection. No clear correlation was found between the relative potency of analogs and their duration of action. Taken together, the results confirm the predominant role of Tyr11 in the inactivation of neurotensin by the brain, but do not support the hypothesis that relative potencies of structural analogs are solely dependent on differing susceptibilities to enzymatic degradation.
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D003864:Depression, Chemical; D007036:Hypothermia, Induced; D007276:Injections, Intraventricular; D008297:Male; D009496:Neurotensin / Q000031:analogs & derivatives / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D009496:Neurotensin