Phencyclidine-like behavioral effects of 2-methyl-3,3-diphenyl-3-propanolamine (2-MDP)

Tang, Alexander; Cangelosi, A.A.; Code, Robert A.; Franklin, Stanley R.

doi:10.1016/0091-3057(84)90244-2

Cited by 11 publications

(3 citation statements)

References 15 publications

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“…Three new structurally different classes of phencyclidine‐like compounds were published during the course of the above studies. Benz(f)isoquinolines (Mendelsohn et al ., ), 2‐methyl‐3,3‐diphenyl‐3‐propanolamine (2‐MDP; Tang et al ., ) and dizocilpine (MK‐801) shared binding and behavioural properties with phencyclidine (Wong et al ., ; Sircar et al ., ; Koek et al ., ). All three showed selective NMDA receptor antagonism: the NMDA receptor antagonist profile within the benz(f)isoquinolines correlated with their phencyclidine‐like properties (Berry and Lodge, ) as did the threefold greater potency of (−)‐, versus (+)‐, 2‐MDP (Blake et al ., ).…”

Section: The Nmda Receptor and Other Psychotomimeticsmentioning

confidence: 99%

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

Lodge

Mercier

2015

British J Pharmacology

154

102

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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. ACh receptors (muscarinic) GluN2BCannabinoid receptors GluN2C D2 receptor GluN2DMetabotrophic glutamate receptors Kainate receptors These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,d Alexander et al., 2013a. PreambleIn April 1981, Nabil Anis and David Lodge showed for the first time that ketamine was a selective antagonist of the NMDA subtype of glutamate receptor. Unlike the discovery of bicuculline as a GABA antagonist, reported by Graham Johnston in an earlier publication in this series of historical reviews (Johnston, 2013), the editors of Nature were not impressed, the finding 'not being of sufficient general interest'. Fortunately, the British Journal of Pharmacology took a different view and the resulting paper has now over 1000 citations . Both before and since this discovery, ketamine and its congener, phencyclidine, have captured the interest of clinicians, basic scientists and sections of the general public. This review will attempt to describe some of this history and bring the reader up to date with the latest twists of this fascinating story in the context of these drugs as NMDA receptor antagonists. Discovery of phencyclidine and ketamine: early observationsAbout 27 years earlier, phencyclidine had been synthesized by chemists at Parke Davis Company but not published for some 10 years (Maddox et al., 1965). Initial pharmacology, however, was described by Chen et al. (1959) who noted lack of sensation, hyperlocomotion, ataxia and catalepsy in rats and pigeons. They ascribed these to monoaminergic mechanisms and showed partial reversal by the neuroleptic chlorpromazine (Chen et al., 1959). At about the same time, Ed Domino commenced a fuller study of the neuropharmacology of phencyclidine (Domino, 1964). In rats, he described a 'drunken state' with increased locomotor activity leading to ataxia and catatonia at higher doses. Dogs also showed a similar state called 'canine delirium, although in monkeys a more satisfactory anaesthetic state was ...

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Section: The Nmda Receptor and Other Psychotomimeticsmentioning

confidence: 99%

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

Lodge

Mercier

2015

British J Pharmacology

154

102

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“…An unusual facet of the C5 SAR is brought into play by the observation that 2-aminoethyl derivative 21 (X¡ = 20 nM) retains high receptor affinity. Although 21 possesses chain length at C5 equivalent to the propyl compound 5 (X¡ = 1100 nM), it has a receptor affinity approximately 50 times that of the alkyl. This represents a recovery of 1.75 kcal of the 2 kcal apparent binding energy lost on extending the side chain from ethyl to propyl (see above).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and structure-activity relationship of C5-substituted analogs of (.+-.)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine [(.+-.)-desmethyl-MK801]: ligands for the NMDA receptor-coupled phencyclidine binding site

Monn¹,

Thurkauf²,

Mattson³

et al. 1990

J. Med. Chem.

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A series of eight C5-substituted analogues of (+-)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (1) have been prepared by the directed lithiation-alkylation (and acylation) of its (+-)-N-tert-butylformamidinyl derivative 2 followed by formamidine solvolysis. An additional 10 analogues were prepared by elaboration of the C5-ethyl ester derivative. Analogues possessing large (e.g. propyl and larger) lipophilic substituents displace [3H]-1-(1-thienylcyclohexyl)piperidine [( 3H]TCP) from the high-affinity phencyclidine (PCP) binding site in rat brain homogenates only at high concentrations (Ki greater than 1000 nM); however, the presence of a polar amino functionality (e.g. 2-aminoethyl) offsets this effect (Ki = 20 nM). Thus, the boundary condition for lipophilic substituents larger than ethyl appears to be polar in nature. Interaction of the 11 relatively small (MR less than 14) C5-substituted analogues of 1 with the high-affinity PCP binding site associated with the N-methyl-D-aspartate (NMDA) receptor is best described by the equation log (1/Ki) = -5.83F + 0.64 pi + 7.41 (r = 0.90).

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“…Drug discrimination studies in rats, monkeys, pigeons, etc, have, however found many drugs that do generalize to the PCP and ketamine cues. In the early 1980s, it became apparent that PCP and ketamine provided similar cues to other arylcyclohexylamines such as tiletamine, to benzomorphan sigma opiates such as SKF10,047 and cyclazocine, to dioxalanes such as dexoxadrol and etoxadrol, to morphinans such as dextrorphan and dextromethorphan, to benz(f)isoquinolines and to propanolamines such as 2-MDP (Brady and Balster, 1981;Brady et al, 1982a;1982b;Herrling et al, 1981;Holtzman, 1982;1980;Mendelsohn et al, 1984;Shannon, 1982a;1982b;1981;Tang et al, 1984;J. M. White and Holtzman, 1982).…”

Section: Introductionmentioning

confidence: 99%

Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

et al. 2018

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Ketamine, a channel blocking NMDA receptor antagonist, is used off-label for its psychedelic effects, which may arise from a combination of several inter-related actions. Firstly, reductions of the contribution of NMDA receptors to afferent information from external and internal sensory inputs may distort sensations and their processing in higher brain centres. Secondly, reductions of NMDA receptor-mediated excitation of GABAergic interneurons can result in glutamatergic overactivity. Thirdly, limbic cortical disinhibition may indirectly enhance dopaminergic and serotonergic activity. Fourthly, inhibition of NMDA receptor mediated synaptic plasticity, such as short-term potentiation (STP) and long-term potentiation (LTP), could lead to distorted memories. Here, for the first time, we compared quantitatively the effects of ketamine on STP and LTP. We report that ketamine inhibits STP in a double sigmoidal fashion with low (40 nM) and high (5.6 μM) IC values. In contrast, ketamine inhibits LTP in a single sigmoidal manner (IC value ∼ 15 μM). A GluN2D-subunit preferring NMDA receptor antagonist, UBP145, has a similar pharmacological profile. We propose that the psychedelic effects of ketamine may involve the inhibition of STP and, potentially, associated forms of working memory. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

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Phencyclidine-like behavioral effects of 2-methyl-3,3-diphenyl-3-propanolamine (2-MDP)

Cited by 11 publications

References 15 publications

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

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

Synthesis and structure-activity relationship of C5-substituted analogs of (.+-.)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine [(.+-.)-desmethyl-MK801]: ligands for the NMDA receptor-coupled phencyclidine binding site

Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity

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