Bioorganic and Medicinal Chemistry p. 1503 - 1513 (2000)
Update date:2022-08-05
Topics:
Ronsisvalle, Giuseppe
Marrazzo, Agostino
Prezzavento, Orazio
Pasquinucci, Lorella
Falcucci, Barbara
Di Toro, Rosanna
Spampinato, Santi
A series of 1-phenyl-2-cyclopropylmethylamines structurally related to (+)- and (-)-MPCB were synthesized and their binding affinities for σ1, σ2, opioid and dopamine (D2) receptors were evaluated. Substitution of the cis-N-normetazocine with different aminic moieties provided compounds with high affinity and selectivity for σ binding sites with respect to opioid and dopamine (D2) receptors. The observed increase in σ2 affinity as compared to the parent (+)-MPCB, supports the idea that the particular stereochemistry of (+)-cis-N-normetazocine affects σ1 selectivity but does not affect σ1 affinity. The (±)-cis isomers of methyl 2-[(1-adamantylamino)methyl]-1-phenylcyclopropane-1-carboxylate (18) displayed a higher affinity and selectivity for the σ1 and σ2 receptor subtypes compared to the (±)-trans 19. Interestingly, the enantiomer (-)-cis 18 displayed a preference for σ1 receptor subtype whereas the (+)-cis 18 did for σ2. These results prompt us to synthesize compounds with modification of nitrogen and carboxyl groups. The compounds obtained showed high affinities and selectivity for σ sites. Moreover, modifications of carboxyl groups provided compounds with the highest affinities in the series. In particular, compound 25 with reverse-type ester showed a K(i) of 0.6 and 4.05nM for σ1 and σ2 binding sites, respectively. Copyright (C) 2000 Elsevier Science Ltd.
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