Nitrocaramiphen hydrochloride

Caramiphen, iodocaramiphen and nitrocaramiphen are potent, competitive, muscarinic M1 receptor-selective agents.[Pubmed:8449241]

Eur J Pharmacol. 1993 Feb 16;231(3):485-8.

Caramiphen, iodocaramiphen and nitrocaramiphen were examined for affinity at the muscarinic M1, M2 and M3 receptor subtypes in radioligand binding assays. Caramiphen binds with high affinity at the M1 site labeled by [3H]pirenzepine in rat cortex (Ki = 1.2 nM) and displays a 27-fold greater preference for the M1 than the M2 site labeled by [3H](-)-quinuclidinyl benzilate in rat heart, and a 6-fold greater preference for the M1 than the M3 site labeled by [3H]N-methylscopolamine in rat submaxillary gland. Iodocaramiphen binds with high affinity (Ki = 2.1 nM) and selectivity (59-fold) for the M1 vs. M2 subtype, and is 4-fold more selective for the M1 vs. M3 site. Nitrocaramiphen binds with high affinity for M1 sites (Ki = 5.5 nM) and with a 71-fold selectivity over M2, and a 10-fold selectivity for the M1 over the M3 subtype. All three compounds interacted with the M1 binding site in a competitive manner. Nitrocaramiphen and iodocaramiphen are as potent and showed a comparable selectivity for binding to the M1 over the M2 site than the prototypical agent pirenzepine (M1; Ki = 5.2 nM, 51-fold selectivity). Additionally, nitrocaramiphen demonstrates at least a 10-fold selectivity for the M1 over the M3 site. These ester-type antimuscarinics may be better ligands for the study of M1 receptors in brain than the hydrophilic agent pirenzepine.

Muscarinic receptor binding profile of para-substituted caramiphen analogues.[Pubmed:1920350]

J Med Chem. 1991 Oct;34(10):2984-9.

Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).