Ketamine and phencyclidine: the good, the bad and the unexpected

Abstract

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms.

Figure 1

Original record from Anis et al. (1983) showing one of the earliest experiments demonstrating the selectivity of ketamine for NMDA. The recording shows the firing rate of a spinal neurone from a pentobarbitone-anaesthetized cat in response to the electrophoretic ejection of quisqualate, kainate and N-methyl-DL-aspartate. The co-ejection of ketamine almost abolishes the latter with only minor effects on responses to the non-NMDA receptor agonists and recovery occurs within 5 min of stopping the ketamine ejection. Other details are in Anis et al. (1983).

Figure 2

Chemical structure of some channel-blocking NMDA antagonists.

Figure 3

Stereoselective potency between pairs of isomers as NMDA receptor antagonists versus their stereoselectivity in phencyclidine-like binding assays (A) and in drug discrimination assays (B). Data are compiled from references cited in the text, showing potency comparisons between isomers (e.g. Berry et al., 1984a,b,; Church et al., 1985; 1991,). Each numbered point represents the stereoselectivity of the following pairs of isomers: 1 = (−) versus (+) s-cyclazocine: 2 = dexoxadrol versus levoxadrol: 3 = (+) versus (−) 3-methylphencyclidine: 4 = dextrorphan versus levorphanol: 5 = (+) versus (−) SKF10,047: 6 = (−) versus (+) α-cyclazocine: 7 = (+) versus (−) ketamine: 8 = (−) versus (+) 2-MDP: 9 = (−) versus (+) pentazocine β.

Figure 4

Comparison of potency of structurally diverse compounds, expressed relative to phencyclidine, as NMDA receptor antagonists in vitro versus relative potency in binding assays (A) and as NMDA receptor antagonists in vivo versus relative potency in drug discrimination assays (B). Data are compiled from references cited in the text; potencies were compared in the same animals and often on the same neurones (e.g. Berry et al., ; Church and Lodge, 1990). Each numbered point represents a single compound: 1 = MK-801: 2 = (−)-β-cyclazocine: 3 = thienylcyclohexylpiperidine: 4 = phencyclidine: 5 = LY154045: 6 = α-cyclazocine: 7 = dextrorphan: 8 = SKF10,047: 9 = ketamine: 10 = (+)-s-cyclazocine: 11 = pentazocine: 12 = LY154005: 13 = dexoxadrol: 14 = dextromethorphan: 15 = levorphanol: 16 = levoxadrol: Note that the compounds plotted in (A) are not identical to those in (B).

Figure 5

Historical development of crude models of NMDA receptor-channel complexes with putative sites of action of key compounds. (A) and (B) were used by Lodge at conferences during the 1980s and 1990s, respectively, reflecting his knowledge of structure function early in each decade. (C) reflects current ideas showing the relationship of the amino terminal (ATD), ligand binding (LBD) and transmembrane (TMD) domains with putative binding sites for negative allosteric (N; e.g. ifenprodil), positive allosteric (P; e.g. pregnenolone) and channel-blocking (C; e.g. ketamine) compounds, kindly provided by David Jane and www.hellobio.com.

Figure 6

Newer diarylethylamine street drugs, like ketamine, reduce NMDA receptor-mediated synaptic excitation. The graphs plot the amplitude of field EPSPs in the CA1 region of a hippocampal slice following stimulation of the Schaffer collateral input. Slices had been treated with AMPA and GABA receptor antagonists to isolate the NMDA receptor component of the synaptic event. The top graph is a single experiment showing the effect of ketamine 10 μM and D-AP5 100 μM, demonstrating that these were NMDA receptor-mediated responses. The inset shows the raw traces. The subsequent three graphs show pooled data from four or five experiments illustrating NMDA receptor antagonism by ketamine, 2-methoxy-diphenidine and diphenidine. Note the slower time course to reach near plateau reduction of the EPSP. These data suggest that diphenidine is somewhat more potent than 2-methoxydiphenidine, which in turn is more potent than ketamine.