SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 4A-PHENANTHRENAMINE DERIVATIVES ACTING AT THE PHENCYCLIDINE BINDING-SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX

A novel series of octahydrophenanthrenamines and their heterocyclic an alogues have been synthesized as potential noncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptor complex. The compounds wer e evaluated for their affinity at the phencyclidine (PCP) binding site by determining their ability to displace [H-3]TCP from crude rat brai n synaptic membranes. A wide range of affinities were observed, with t he most potent analogs possessing IC50's equivalent to that of the ref erence agent MK-801 (3,dizocilpine). NMDA antagonist activity was demo nstrated by prevention of glutamate-induced accumulation of [Ca-45(2+) ] in cultured rat cortical neurons. Selected compounds were also studi ed in vivo to determine their ability to prevent the lethal effects of systemically injected NMDA in the mouse. In general, the SAR of the p henanthrenamine series may be summarized as follows: (a) for the amino group at C4a, NHMe > NH2 > NHEt much-greater-than NC5H10; (b) for the B-ring substitution, X = CH2 > S > 0; (c) unsaturation of the C ring decreases receptor affinity; (d) cis-ring fusion between the B and C r ings is desirable; (e) 6-hydroxy or 6-methoxy substitution of the phen anthrenamine system identified an additional hydrogen bonding interact ion that substantially increased receptor affinity; (f) spiro analogue s (such as 55, IC50 = 3400 nM), which altered the point of attachment of the C ring, caused a substantial reduction in PCP-site affinity. Mo lecules from this series were useful for refining a pharmacophore mode l consistent with previous models of the PCP site. In this model, the (R)-(+)-phenanthrenamine 13 superimposes closely onto MK-801 (3), and the angular 4a-amino group is believed to hydrogen bond with a putativ e receptor site atom. In the phenanthrenamine and thiaphenanthrenamine series, the (R)-(+)-enantiomers (9, 13, and 44) are more potent by ap proximately 5-10-fold than their corresponding (S)-(-)-enantiomers wit h respect to their affinity for the PCP site, their ability to prevent accumulation of [Ca-45(2+)] in cultured neuronal cells, and their pro tection against the lethal effects of NMDA in mice. In general, there was no separation between the dose that prevented NMDA lethality and t he dose that produced ataxia in mice, except in the case of the thiaph enanthrenamines 41 and 43. We have not yet obtained evidence that this small separation in activity offers a therapeutic advantage in the tr eatment of cerebral ischemia or other neurodegenerative disorders.