Biomedical subjects
Publications and source records attributed to R B Raffa.
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The subject of 'drug addiction' is multifaceted and many aspects of it (even some of the definitions) are controversial. Collateral medical problems include the spread of HIV and hepatitis C virus secondary to i.v. drug abuse and effects on prenatal brain development (1). Progress in the understanding of the causes of addictions and its treatment has been impeded by the lack of a unifying biochemical theory. However, recent evidence suggests that some common mechanism might underlie addictions to otherwise apparently unrelated drugs. A major hypothesis has emerged suggesting that the neurotransmitter dopamine (DA) might play a central role in the molecular mechanisms of at least some addictions. If so, it would represent an important target for discovery of effective pharmacotherapy and revolutionize the pharmacist's role in treating addictions. This short overview outlines the status of the theory of a common biochemical mechanism of drug addiction.
A series of (imidazolylmethyl)oxazoles and -thiazoles were prepared and evaluated as alpha(2) adrenoceptor agonists. These compounds were also tested in in vivo paradigms that are predictive of analgesic activity. Variations in both the imidazole and thiazole portions of the molecule were investigated. Some of the more potent compounds such as 22, 26, 45, and 53 displayed alpha(2) receptor binding in the 10-20 nM range and also had significant antinociceptive activity in the mouse abdominal irritant test (MAIT).
The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.
Intracerebroventricular (i.c.v.) administration to mice of delta9-tetrahydrocannabinol (delta9-THC), WIN 55,212-2 or the endogenous cannabinoid anandamide induced dose-related antinociception in the 55 degrees C warm-water tail-flick test. Pretreatment (24 h, i.c.v.) with pertussis toxin dose-dependently reduced the antinociceptive effect of delta9-THC (955 nmol), WIN 55,212-2 (30 nmol) and anandamide (135 nmol) (IC50 = 0.13, 5.5, and 0.32 nmol, respectively). In contrast, pretreatment (24 h, i.c.v.) with cholera toxin (0.1-3.0 mg) reduced the antinociception of WIN 55,212-2, had minimal effect on delta9-THC, and dose-dependently increased the antinociception of anandamide (ED50 = 0.50 nmol). These data suggest differences in the receptor-effector coupling of delta9-THC, WIN 55,212-2 and anandamide in supraspinal-induced antinociception in mice.
A core concept in pharmacology is drug-receptor affinity, i.e., the tendency of a drug molecule to bind to one or more receptors due to the collective influence of multiple molecular forces. The estimation of affinity as a dissociation constant (reciprocal of the equilibrium constant) is extraordinarily valuable. However, elucidation of the nature of the underlying concept--i.e., what accounts for affinity--is not achievable using such a static measure. Observing how the system responds to a perturbation (e.g., to a change in temperature) reveals more fundamental information. The present review summarizes the general concepts of thermodynamic analysis applied to drug-receptor interactions and discusses 'extrathermodynamic' phenomena, such as enthalpy-entropy 'compensation'. Together, these concepts may provide insight into the nature of drug-receptor interactions, begin to elucidate the forces that underlie such interactions--and begin to define and refine more nebulous terms such as affinity.
Several lines of evidence implicate the neuropeptide substance P in depression, either in the pathogenesis or as a novel target for amelioration of symptoms. NK1 (substance P) receptor antagonists have been reported to have antidepressant-like actions in animal models. The first clinical trial of an NK1 antagonist showed promising results. A second trial, using a more potent compound, is underway. If the clinical trials show that NK1 (substance P) antagonism represents a well-tolerated, distinct mechanism for antidepressant activity, novel antidepressant agents will emerge as mono- or adjunct-therapy.
OBJECTIVE: To review preclinical and clinical information related to pharmacologic modulation of dopamine D2 receptors as potential novel antipsychotic therapy. Specifically, to summarize the data that suggest a modulatory action of adenosine A2A receptors on dopamine D2 receptors and, therefore, a possible rational role of adenosine A2A agonists as novel antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to May 1998) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: For all of the older and many of the newer antipsychotic agents, there is a strong correlation between clinical antipsychotic activity and affinity for dopamine D2 receptors. Unfortunately, dopamine D2 receptors are believed to also be involved in the adverse effect profile of these agents. The indirect modulation of dopamine D2 receptors, rather than direct block, might produce antipsychotic effects without the usual adverse reactions. Several lines of evidence from animal studies suggest that the use of selective A2A agonists might represent a novel approach to the treatment of psychoses. CONCLUSIONS: Dopamine receptor modulation might represent a novel antipsychotic approach or adjunct therapy. The data regarding adenosine agonists (particularly selective A2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.
Graded doses of morphine sulfate and clonidine hydrochloride were administered intrathecally to mice that were then tested for antinociception in the 55 degrees C tail immersion test. The dose-effect relations of each compound were used in calculations that permitted the construction of a three-dimensional plot of the expected additive effect (vertical scale) against the planar domain of dose pairs representing combinations administered simultaneously. This additive response surface became the reference surface for viewing the actual effects produced by three different fixed-ratio combinations of the drugs that were used in our tests. Each combination produced effects significantly greater than indicated by the additive surface, thereby illustrating marked synergism and a method for quantifying the synergism. This quantification, measured by the value of the interaction index (alpha), was found to be dependent on the fixed-ratio combination; accordingly, the actual response surface could not be described by a single value of the index alpha. Furthermore, we found that application of the common method of isoboles gave estimates of the index that agreed well with those obtained from the more extensive surface analysis. These results confirm earlier studies, which found synergism for these drugs while also providing surface views of additivity and synergism that form the basis of isobolographic analysis.
The apparent thermodynamic parameters of binding of ten ligands to the cloned rat mu-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the Kd or Ki values at 0 degrees C, 12 degrees C, 25 degrees C and 37 degrees C were determined, a van't Hoff plot was generated and deltaH degrees' , deltaS degrees' and -TdeltaS degrees' and deltaG degrees' were calculated. Changes in free energy (deltaG degrees') ranged from -10.35 to -15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-penicillamineThr-NH2 (CTAP) was endothermic (deltaH degrees' > 0) and driven by an increase in entropy (-TdeltaS degrees' = -13.08 to -18.57 kcal/mol). The binding of naltrexone was exothermic (deltaH degrees' = -12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) was exothermic (deltaH degrees' = -3.53 to -9.95 kcal/mol) and occurred with an increase in entropy (-TdeltaS degrees' = -2.48 to -7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy-entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the mu receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.
The mechanism of the antidepressant action of St. John's wort (Hypericum perforatum) remains unknown. A central component similar to that of the other clinically-popular antidepressants (e.g., inhibitors of 5-HT or norepinephrine reuptake or MAO) is suspected to play a role, but other mechanisms distinct from the SSRIs, NSRIs or MAOIs are possible. The extract of St. John's wort that is used clinically consists of multiple compounds. Hypericin is believed to be one of the major components responsible for the antidepressant effect. In the present study, the affinity of hypericin was determined at thirty receptor or reuptake sites. At 1.0 microM, hypericin inhibited less than 40% of specific radioligand binding at all sites except mAChR and sigma receptors. The demonstration of sigma receptor binding of hypericin is a novel finding and it might contribute to a new understanding of the clinical attributes of St. John's Wort.
The present review is an attempt to summarize the diverse literature that suggests a role for neurokinins in a variety of CNS developmental or disease processes. The role of neurokinins in (anti)nociception is well known and is the subject of other comprehensive reviews. The focus of this review is on associations that implicate substance P or other neurokinins in certain aspects of CNS development and in various neuropathologic disorders that have neurodegenerative, psychiatric or other clinical manifestations. Also included are associations related to the central control of some "peripheral" functions. The amount of and degree of evidence for neurokinin involvement in each situation vary from strong to speculative--critical analyses and commentaries on individual methodologies and studies are available from other sources. When viewed in this broad context, the information suggests intrinsic neuroprotective or neurodegenerative properties of neurokinins. It is proposed that these properties delineate a specialized area within the broader field of neurokinin research.
FMRFamide (Phe-Met-Arg-Phe-NH2) and several analogs produce centrally-mediated, naloxone-reversible antinociception, but have minimal affinity for opioid receptor (sub)types. In the present study, the antinociception in mice (55 degrees C tail-flick test) produced by supraspinal (intracerebroventricular; i.c.v.) administration of [D-Met2]-FMRFamide (a stable analog of FMRFamide) was attenuated by pretreatment with i.c.v. oligodeoxyribonucleotide antisense to the opioid mu receptor or by antisense to the Gi2alpha G-protein subunit. These data suggest that [D-Met2]-FMRFamide produces its antinociception via an opioid interneuron.
OBJECTIVE: To review preclinical information related to possible antidepressant mechanism(s) of action of St. John's wort in order to address the issue of whether its purported clinical effectiveness has a rational pharmacologic basis. DATA SOURCES: Primary and review articles were identified by a MEDLINE search (1966-January 1998) and through secondary sources. Many of the original German articles had English abstracts, but where necessary, German articles were translated into English. The results of a new screen of hypericin activity at receptor and uptake sites are summarized. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: The neuropharmacology of St. John's wort has been examined in only a few studies. A mechanism similar to that of the synthetic antidepressants, such as the selective serotonin-reuptake inhibitors or monoamine oxidase (MAO) inhibitors, might play a role, but other mechanisms are possible. CONCLUSIONS: Hypericum extracts have only weak activity in assays related to mechanisms of the synthetic antidepressants, that is, inhibition of MAO, catechol O-methyltransferase, or serotonin reuptake. It has been postulated that the clinical efficacy of St. John's wort could be attributable to the combined contribution of several mechanisms, each one too weak by itself to account for the overall effect. The recent demonstration of a significant affinity of hypericin for sigma receptors presents new possibilities for consideration.
The hypothesis that mu-opioid agonists having low antinociceptive efficacy might be more susceptible to interference with G-protein coupling than mu-opioid agonists having higher antinociceptive efficacy was tested. Supraspinal antinociceptive efficacy for the three mu-opioid agonists morphine, [D-Ala2, NMePhe4, Gly5-ol]-enkephalin (DAMGO) and sufentanil in the mouse 55 degrees C warm-water tail-flick test was evaluated 18-24 h after intracerebroventricular (i.c.v.) administration of beta-funaltrexamine (beta-FNA). The beta-FNA pretreatment (0.2-2.0 nmol) attenuated antinociception in the order morphine > DAMGO > sufentanil, consistent with previous reports of their relative antinociceptive efficacy. The association of efficacy with G-protein coupling was then assessed by determining sensitivity to i.c.v. (0.1-3.0 micrograms) pertussis toxin (PTX) or cholera toxin (CTX). The effect of PTX on equiantinociceptive doses was in the inverse order of agonist efficacy. CTX augmented sufentanil-induced antinociception. Morphine- and DAMGO-induced antinociception were unaffected by CTX. These data suggest that: (i) highly efficacious mu agonists (viz., sufentanil) couple more efficiently to PTX-sensitive inhibitory Gi-proteins than do agonists of lower efficacy (viz., morphine, DAMGO) and (ii) highly efficacious mu agonists have greater capacity to utilize CTX-sensitive stimulatory Gs-proteins than do mu-agonists with lower efficacy.
Distinguishing between pharmacologically additive and synergistic drug combinations requires experimental designs and statistical analyses that often require appreciable numbers of animals and much experimenter time. The current study employed a design in which individual dose-effect data from each drug were translated into theoretically additive total dose combinations, in a fixed drug proportion, in order to produce a composite additive dose-effect relation that could be compared with that of an actual mixture having the same proportion. Results from this approach, using a combination of intrathecal doses of morphine and clonidine, were virtually identical to those using isobolographic analysis of the same data set. Both analyses showed significant synergism for this combination and, in each method, it was not necessary to constrain the drug regression lines to parallelism. In contrast to the isobole approach, the use of the composite additive dose-effect relation also allows observation of the interaction over a range of effects while reducing the size of the data sets needed.
Tramadol hydrochloride is a centrally acting synthetic analgesic in widespread clinical use. Despite different degrees of opioid-like characteristics in preclinical tests, it is characterized by lack of full naloxone reversibility or naloxone-precipitated withdrawal in humans. To investigate this apparent discrepancy, the present study measured the affinity of tramadol (and its enantiomers) and an active O-desmethyl metabolite (M1) (and its enantiomers) to cloned human opioid receptors of the mu, delta and kappa type stably expressed in HN9.10 neuroblastoma cells. At mu sites, the Ki values for tramadol, its (+) and (-) enantiomers, M1, and its (+) and (-) enantiomers were 17000, 15700, 28800, 3190, 153 and 9680 nM, respectively, compared to 7.1 nM for morphine. These results are consistent with the suggestion of a non-opioid contribution to the clinical profile of tramadol.