Cyclic
Enkephalins with a Diversely Substituted Guanidine Bridge or a Thiourea
Bridge: Synthesis, Biological and Structural Evaluations
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Abstract
Two
series of 22 and 15 atom cyclic enkephalins incorporating a diversely
substituted guanidine bridge have been prepared to assess the potential
effect of the bridge substitutions on their opioid activity profile.
The most notable results were obtained with the shortest cyclic analogues,
which showed a significant variation of their binding affinity toward
μ and δ opioid receptors in relation to bridge substitution.
NMR studies were performed to rationalize these data. Some small analogues
were found to exist as at least one major and one minor stable forms,
which could be separated by chromatography. In particular, the compounds <b>13</b> and <b>14</b> with a cyclic substituent were separated
in three isomers and the basis of this multiplicity was explored by
2D NMR spectroscopy. All compounds were agonists with slight selectivity
for the μ opioid receptor. Compounds <b>7a</b> (thiourea
bridge) and <b>10a</b> (<i>N</i>-Me-guanidine bridge)
showed nanomolar affinity toward μ receptor, the latter being
the more selective for this receptor (40-fold)