Asher Kalir

Interaction of phencyclidine and its new adamantyl derivatives with muscarinic receptors.

Abstract The antimuscarinic potency of new derivatives of phencyclidine containing the adamantyl moiety was evaluated in the guinea pig ileum test. The drugs tested competitively inhibited the acetylcholine-induced contractions. K d values were calculated and compared to those obtained by direct binding to the muscarinic receptors from mouse brain. The new derivative, |1-(2-phenyl-2-adamantyl) piperidine| was found to be the most potent muscarinic antagonist among the many phencyclidine derivatives known to date. The results are discussed in terms of the acetylcholine-like molecular arrangement of these derivatives that gives rise to a characteristic muscarinic interaction.

Species differences determine azido phencyclidine labeling pattern in desensitized nicotinic acetylcholine receptors

Acetylcholine receptor enriched membranes from Torpedo ocellata, Torpedo marmorata and Torpedo californica were studied using [3H] azido-phencyclidine (AZ-PCP). [3H]-PCP binding to receptors from all three species revealed marked similarities. Photoaffinity labeling by [3H]-AZ-PCP resulted in the tagging of mainly alpha, beta and delta subunits in all species. When carbamylcholine was added, it enhanced the labeling of beta subunits in T. ocellata, delta in T. marmorata and alpha in T. californica, suggesting species differences in the photolabeling pattern. Multiple homologous binding sites for PCP between the receptor subunits would allow small variations in receptor structure to be manifested in labeling by AZ-PCP, with no differences in binding and functional properties of the receptors.

Receptor binding and antinociceptive properties of phencyclidine opiate-like derivatives.

The relative potencies of a new series of phencyclidine (PCP) analogs for the displacement of [3H] morphine binding from rat brain homogenates are well correlated with the relative antinociceptive potencies in the test of writhing induced by acetic acid (0.6%). One group of compounds exerts a completely naloxone-reversible analgesic effect, while the effects of a second group are partially reversed by naxolone. These findings and the structural differences between the two groups suggest that their analgesic is mediated through different opiate receptors.

On the opioid nature of phencyclidine and its 3-hydroxy derivative☆

Phencyclidine (PCP) and its 3-hydroxy derivative (PCP-3-OH) caused a dose-dependent, naloxone reversible inhibition of the response of the guinea pig ileum to electrical stimulation. Unlike PCP, PCP-3-OH exerted an opioid antagonistic effect in the mouse vas deferens bioassay. Whereas both compounds displayed a high affinity in displacing [3H]SKF-10047 binding to rat brain membranes, PCP-3-OH displayed a high affinity to [3H]morphine receptors also. The mediation of alpha- and mu-receptors in the opioid effects of these drugs is discussed.

Characterization of the Interaction of Phencyclidine and its Derivatives with the Ionic Channel of the Nicotinic Receptor

(3H)-Phencyclidine (PCP) binds specifically to the cholinergic ionophore in synaptic membranes prepared from Torpedo electric organ. Experiments performed by the centrifugation method establish that the binding is saturable, reversible and selective and can be characterized by a single dissociation constant (3.6 +/- 1.8 microM). The maximal binding capacity is 600 +/- 150 pmol/mg of membrane protein. Bound (3H)-PCP can be displaced by unlabelled PCP and a series of its derivatives. The reactivity of PCP derivatives in binding to (3H)-PCP binding sites, as related to structural changes at the phenyl, piperidyl and cyclohexyl moieties, is discussed.