Benjamin Weiss (January 26, 1937) is an American neuropharmacologist, Emeritus Professor of Pharmacology and Physiology at Drexel University College of Medicine. He is best known for his work with cyclic nucleotide phosphodiesterases. He was the first to propose, based on his experimental work, that selective inhibition of phosphodiesterases which are expressed differentially in all tissues, could be used as a target for drug development. His work is the basis for many marketed and developmental human drugs that selectively inhibit cyclic nucleotide phosphodiesterases.
His investigations on the modulation of adrenergic responses in the pineal gland have resulted in the formation of new concepts that may explain the phenomena of drug tolerance and drug hypersensitivity. He and his laboratory were also instrumental in the development of antisense oligonucleotides and antisense RNA as pharmacological tools to study calmodulin and dopamine receptors, and as pharmacological agents for antisense therapy in brain and other tissue.
Early life and education
Weiss was born in The Bronx in 1937 and was raised on a chicken farm in New Jersey where his immigrant parents moved in 1946. Weiss went to Toms River High School, graduating in 1954. He received his undergraduate degree in Pharmacy in 1958 from the Philadelphia College of Pharmacy and Science (now, University of the Sciences), where he also earned a M.Sc. in 1960 and a Ph.D. in Pharmacology in 1963, under the tutelage of G. Victor Rossi. From 1963 to 1966 he had a Postdoctoral Fellowship and a Staff Fellowship at the National Heart Institute, National Institute of Health, where he studied under Bernard B. Brodie. He did further training as a research associate at Columbia University, College of Physicians and Surgeons, with Erminio Costa from 1966 to 1968.
Personal life
In 1959 Weiss married Joyce Zelnick. They have three children and five grandchildren.
Scientific career
From 1968 to 1972 Weiss worked at the National Institute of Mental Health at St Elizabeths Hospital, Washington, D.C., where he held the position of chief of the Section on Neuroendocrinology. In 1972 he accepted the position of professor of pharmacology at the Medical College of Pennsylvania (MCP), where he held the positions of professor of pharmacology and psychiatry, and chief of the Division of Neuropsychopharmacology. He was also a visiting scientist at the Mario Negri Institute for Pharmacological Researchin Milan, Italy, and a visiting scientist at the Weizmann Institute of Science in Rehovot, Israel. On retirement in 1999 he became an emeritus professor in the Department of Pharmacology and Psychiatry at MCP. In 2002, when Drexel University assumed leadership of MCP, he was given the position of professor emeritus in the Department of Pharmacology and Physiology at Drexel University College of Medicine, the position he now holds.
Publications
Weiss is the editor of two books: (Weiss, Benjamin, ed., Cyclic Nucleotides in Disease[1]), and Antisense Oligodeoxynucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents[2)). He has also published over 300 scientific articles, reviews and abstracts on his research in molecular biology and molecular pharmacology.
Research
Cyclic Nucleotide Phosphodiesterases:
Weiss and co-workers developed rapid phosphodiesterease assays [3, 4], separated different isozymes of phosphodiesterase in various tissues by electrophoretic methods [5,6]and showed that drugs could selectively inhibit the several isozymes of phosphodiesterase (link) isozymes. He showed that a single cell type may contain more than one form of phosphodiesterase [6,7] and that different forms of phosphodiesterase could be induced or activated by certain neurohormones(e.g. norepinephrine) [7]and intracellular proteins (e.g. calmodulin) [8,9]. He demonstrated that there are different forms of phosphodiesterase in different tissues including the mammalian brain [5,6]and lung [10].
Weiss was the first to show that phosphodiesterase activity is altered in certain disease states [11, 13, 14, 15,16]and to propose that selective inhibition of phosphodiesterase could be the basis of drug selectivity [17,18,19,20]. Weiss and co-workers did extensive work which demonstrated that certain neuropeptides [21,22], alpha adrenergic antagonists [23]and phenothiazineantipsychotic drugs were potent inhibitors of calmodulin activated enzymes [24,25,26,27,28].
Modulation of Adrenergic Receptor-Linked Adenylate Cyclase System: Using the pineal gland as a model, Weiss and his colleagues were the first to show that the beta-adrenergic receptor-linked adenylate cyclasesystem is modified chronically by a variety of physiological factors and pharmacological perturbations [reviewed in 29]. His laboratory demonstrated that this system is influenced by sympathetic neuronal input, in that a long-term decrease in sympathetic input results in an increased responsiveness to adrenergic stimuli [30, 31]; by environmental lighting, in that darkness, which increased sympathetic input to the pineal gland decreases the response to adrenergic input[32]; by hormonal status, in that low estrogen levels increase the responsiveness to norepinephrine[33]and by the age of the animal, in that older animals evidence a decrease in beta-adrenergic receptors and a reduced response to adrenergic stimuli [34,35,36].
Weiss showed additionally that the responses to adrenergic stimuli are also altered by a variety of pharmacological agents that chronically change adrenergic input. For example, long-term treatment with agents that reduce sympathetic input, like reserpine[37], 6-hydroxydopamine[38], guanethidine[39], and certain phenothiazine antipsychotic drugs [40]all increase the density of beta-adrenergic receptors and increase the responsiveness to adenylate cyclase. By contrast, treatment with drugs such as the anti-depressant desmethyimipramine, which increases adrenergic input, reduces the adrenergic receptors [41].These studies show that long-term changes following physiological or pharmacological alterations in adrenergic input may be explained by a common biological principle: the degree to which an adrenergically innervated structure can be stimulated is inversely related to the degree to which it had been previously stimulated. This hypothesis may provide a biochemical basis for explaining the altered responsiveness of the adrenergic system seen in aging and in males vs. females, and may explain the mechanism for drug supersensitivity and drug tolerance.
Antisense Oligonucleotidesand Antisense RNA:Weiss’ laboratory made discoveries on: 1) The role of calmodulin in neuronal differentiation and proliferation; 2) Behavioral and biochemical correlates of dopamineresponses in brain; 3) Development of antisense oligonucleotides and antisense RNA as pharmacological tools to study calmodulin and dopamine receptors, and as pharmacological agents for gene therapy in brain; and 4) Reversal of dopaminergic supersensitivity: preclinical mechanisms and clinical applications. 6) The studies laid the foundation for the therapeutic use of antisense oligonucleotides and antisense RNA in a variety of disease states. A number of drugs are currently on the market and many others are in clinical development using the concept of antisense therapy, including in cancer, Huntington's Disease, and other neurological diseases.
Weiss and his group, assisted by Genoveva Uzunova (Davidkova), who carried out a significant part of the antisense RNA studies in his group, used molecular biological, biochemical, pharmacological, cell biological techniques (cell cultures, fluorescence microscopy), and mouse models, to develop antisense oligonucleotides to the D1 and D2 dopamine receptors. They showed for the first time that intracerebroventricular (i.c.v.) and intrastriatal injection oligonucleotides targeted to the D1 or D2 dopamine receptor in mouse brain can block the biological effects of the targeted receptor with very high specificity and, importantly, without inducing receptor supersensitivity, which is a significant drawback to the conventional neuroleptic drugs such as haloperidol[42,43,44]. Therefore, these novel pharmacological agents would not likely induce the debilitating motor side effects resulting from conventional pharmacological agents..
Since the effects of the oligonucleotides are relatively short-lasting (up to 2–3 days) and it is necessary to inject them repeatedly in mouse brain in order to achieve a long-term reduction in the D2 dopamine receptor mRNA and the dopamine receptor protein, and the concomitant long-term blockade of the behaviors modulated by these receptors, Weiss’ group developed a second approach – expression of D2 dopamine antisense RNA in brain by a non-viral plasmid vector. This approach was the first to show that a single intrastriatal injection of D2dopamine receptor antisense RNA (targeted to the long isoform of the murine D2 dopamine receptor) can effectively block D2 dopamine-mediated behaviors for up to one month [45]. Moreover, this did not induce D2 receptor supersensitivity, unlike the conventional neuroleptic haloperidol, which blocks D2 dopamine receptors and several other subtypes of dopamine receptors [46]. These studies opened up the possibility to develop a new gene therapeutic approachto treat neurologic and psychiatric conditions associated with D2 receptor hyperactivity such as chorea and addiction to alcohol [47]. In a broader perspective, a similar gene therapeutic approach targeting other central nervous system (CNS) neuroreceptors and proteins may prove useful for treating other disorders of the CNS . The antisense RNA approach is an alternative to the RNA interference approach. RNA interference.
During this period, the studies of Weiss and his group were also focused on the use of antisense oligonucleotides [48]and antisense RNA expression vectors to calmodulin [49] ,which is a ubiquitous calcium binding protein in brain encoded by three different genes that give rise to several transcripts. These studies helped to elucidate the essential role of calmodulin in the proliferation and differentiation of nerve cells and suggest a novel approach with the potential for gene therapy of tumors that express high levels of calmodulin, such as gliomas and certain forms of breast cancer. [50,51].
A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use.
A cyclic nucleotide (cNMP) is a single-phosphate nucleotide with a cyclic bond arrangement between the sugar and phosphate groups. Like other nucleotides, cyclic nucleotides are composed of three functional groups: a sugar, a nitrogenous base, and a single phosphate group. As can be seen in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) images, the 'cyclic' portion consists of two bonds between the phosphate group and the 3' and 5' hydroxyl groups of the sugar, very often a ribose.
Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids can be manufactured as single-stranded molecules with any user-specified sequence, and so are vital for artificial gene synthesis, polymerase chain reaction (PCR), DNA sequencing, molecular cloning and as molecular probes. In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression, or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.
A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, phosphodiesterase refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases.
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in response to the binding of membrane-impermeable peptide hormones to the external cell surface.
Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
A phosphodiesterase type 5 inhibitor is a vasodilating drug that works by blocking the degradative action of cGMP-specific phosphodiesterase type 5 (PDE5) on cyclic GMP in the smooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate the corpora cavernosa of the penis, facilitating erection with sexual stimulation, and are used in the treatment of erectile dysfunction (ED). Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of the arterioles within the lungs, two PDE5 inhibitors, sildenafil and tadalafil, are FDA-approved for the treatment of pulmonary hypertension. As of 2019, the wider cardiovascular benefits of PDE5 inhibitors are being appreciated.
Cyclic guanosine monophosphate-specific phosphodiesterase type 5 is an enzyme from the phosphodiesterase class. It is found in various tissues, most prominently the corpus cavernosum and the retina. It has also been recently discovered to play a vital role in the cardiovascular system.
An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded.
Fenoldopam mesylate (Corlopam) is a drug and synthetic benzazepine derivative which acts as a selective D1 receptor partial agonist. Fenoldopam is used as an antihypertensive agent. It was approved by the Food and Drug Administration (FDA) in September 1997.
Nicergoline, sold under the brand name Sermion among others, is an ergot derivative used to treat senile dementia and other disorders with vascular origins. Internationally it has been used for frontotemporal dementia as well as early onset in Lewy body dementia and Parkinson's dementia. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs. Unlike many other ergolines, such as ergotamine, nicergoline is not associated with cardiac fibrosis.
Phosphodiesterase 1, PDE1, EC 3.1.4.1, systematic name oligonucleotide 5′-nucleotidohydrolase) is a phosphodiesterase enzyme also known as calcium- and calmodulin-dependent phosphodiesterase. It is one of the 11 families of phosphodiesterase (PDE1-PDE11). Phosphodiesterase 1 has three subtypes, PDE1A, PDE1B and PDE1C which divide further into various isoforms. The various isoforms exhibit different affinities for cAMP and cGMP.
The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP.
Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.
Dopamine receptor D5, also known as D1BR, is a protein that in humans is encoded by the DRD5 gene. It belongs to the D1-like receptor family along with the D1 receptor subtype.
cAMP-specific 3',5'-cyclic phosphodiesterase 4B is an enzyme that in humans is encoded by the PDE4B gene.
In the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.
Serotonin antagonist and reuptake inhibitors (SARIs) are a class of drugs used mainly as antidepressants, but also as anxiolytics and hypnotics. They act by antagonizing serotonin receptors such as 5-HT2A and inhibiting the reuptake of serotonin, norepinephrine, and/or dopamine. Additionally, most also antagonize α1-adrenergic receptors. The majority of the currently marketed SARIs belong to the phenylpiperazine class of compounds.
N,N-Dimethyldopamine (DMDA) is an organic compound belonging to the phenethylamine family. It is related structurally to the alkaloid epinine (N-methyldopamine) and to the major neurotransmitter dopamine (of which it is the N,N-dimethylated analog). Because of its structural relationship to dopamine, DMDA has been the subject of a number of pharmacological investigations. DMDA has been detected in Acacia rigidula.
Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.
References
1. Weiss, B.: Editor, Cyclic Nucleotides in Disease, University Park Press, Baltimore, MD. 1975.
2. Weiss, B.: Editor: Antisense Oligodeoxynucleotides and Antisense RNA: Novel Pharmacological and Therapeutic Agents CRC Press, Boca Raton, FL. 1997.
3.Weiss B, Lehne R, Strada S. Rapid microassay of adenosine 3',5'-monophosphate phosphodiesterase activity. Anal Biochem. 1972 Jan;45(1):222-35. PMID4333123.
4. Fertel R, Weiss B.: A microassay for guanosine 3',5'-monophosphate phosphodiesterase activity. Anal Biochem. 1974 Jun;59(2):386-98. PMID4365804.
5. Uzunov, P. and Weiss, B.: Separation of multiple molecular forms of cyclic adenosine 3',5'‑monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim. Biophys. Acta 284:220‑226, 1972. PMID 4342220
6. Uzunov, P., Shein, H.M. and Weiss, B.: Multiple forms of cyclic 3',5'‑AMP phosphodiesterase of rat cerebrum and cloned astrocytoma and neuroblastoma cells. Neuropharmacology 13:377‑391, 1974. PMID 4370207
7. Uzunov, P., Shein, H.M. and Weiss, B.: Cyclic AMP phosphodiesterase in cloned astrocytoma cells: norepinephrine induces a specific enzyme form. Science 180:304‑306, 1973. PMID 4349509.
8. Weiss, B., Prozialeck, W., Cimino, M., Barnette, M.S. and Wallace, T.L.: Pharmacological regulation of calmodulin. In: Calmodulin and Cell Functions, Ann. N.Y. Acad. Sci. 356:319‑345, 1980. PMID 6112947
9. Weiss, B., Prozialeck, W.C. and Wallace, T.L.: Interaction of drugs with calmodulin: Biochemical, pharmacological and clinical implications. Biochem. Pharmacol. 31:2217‑2226, 1982. PMID 6127079
10. Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678‑687, 1976. PMID 183099. Hait, W.N. and Weiss, B.: Increased cyclic nucleotide phosphodiesterase activity in leukemic lymphocytes. Nature 259:321‑323, 1976. PMID 183099
11. Hait, W.N. and Weiss, B.: Characteristics of the cyclic nucleotide phosphodiesterases of normal and leukemic lymphocytes. Biochim. Biophys. Acta 497:86‑100, 1977. PMID 14711
12. Hait, W.N. and Weiss, B.: Increased cyclic nucleotide phosphodiesterase activity in leukemic lymphocytes. Nature 259:321‑323, 1976. PMID 175284
13. Levin, R.M. and Weiss, B.: Characteristics of the cyclic nucleotide phosphodiesterases in a transplantable pheochromocytoma and adrenal medulla of the rat. Cancer Res. 38:915‑920, 1978.
14. Weiss, B. and Winchurch, R.A.: Analyses of cyclic nucleotide phosphodiesterases in lymphocytes from normal and aged leukemic mice. Cancer Res. 38:1274‑1280, 1978.
15. Winchurch, R., Hait, W. and Weiss, B.: Cyclic AMP phosphodiesterase activity of murine T and
B lymphocytes. Cell. Immunol. 41:421‑426, 1978.
16. Hait, W.N. and Weiss, B.: Cyclic nucleotide phosphodiesterase of normal and leukemic lymphocytes: kinetic properties and selective alteration of the activity of the multiple molecular forms. Mol. Pharmacol. 16:851‑864, 1979.
17. Levin, R.M. and Weiss, B.: Mechanism by which psychotropic drugs inhibit adenosine cyclic 3',5'‑monophosphate phosphodiesterase of brain. Mol. Pharmacol. 12:581‑589, 1976.
18. Levin, R.M. and Weiss, B.: Binding of trifluoperazine to the calcium‑dependent activator of cyclic nucleotide phosphodiesterase. Mol. Pharmacol. 13:690‑697, 1977. (a)
19. Levin, R.M. and Weiss, B.: Selective binding of antipsychotics and other psychoactive agents to the calcium‑dependent activator of cyclic nucleotide phosphodiesterase. J. Pharmacol. Exp. Ther. 208:454‑459, 1979.
20. Levin, R.M. and Weiss, B.: Specificity of the binding of trifluoperazine to the calcium‑dependent activator of phosphodiesterase and to a series of other calcium‑binding proteins. Biochim. Biophys. Acta 540:197‑204, 1978. (b)
21. Sellinger‑Barnette, M. and Weiss, B.: Interaction of beta‑endorphin and other opioid peptides with calmodulin. Mol. Pharmacol. 21:86‑91, 1982.
22. Barnette, M.S. and Weiss, B.: Interaction of neuropeptides with calmodulin. A structure‑activity study. Psychopharmacol. Bull., 19:387‑392, 1983.
23. Earl CQ, Prozialeck WC, Weiss B.: Interaction of alpha adrenergic antagonists with calmodulin. Life Sci. 1984 Jul 30;35(5):525-34. PMID6146911.
24. Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441‑477, 1977.
25. Weiss, B. and Levin, R.M.: Mechanism for selectively inhibiting the activation of cyclic nucleotide phosphodiesterase and adenylate cyclase by antipsychotic agents. Adv. Cycl. Nucl. Res. 9:285‑304, 1978.
26. Prozialeck, W.C. and Weiss, B.: Inhibition of calmodulin by phenothiazines and related drugs; structure‑activity relationships. J. Pharmacol. Exptl. Therap. 222:509‑516, 1982.
27. Weiss, B., Earl, C. and Prozialeck, W.C.: Biochemical and possible neuropsychopharmacological implications of inhibiting calmodulin activity. Psychopharmacol. Bull., 19:378‑386, 1983.
28. Weiss, B., Prozialeck, W.C. and Roberts‑Lewis, J.M.: Development of selective inhibitors of calmodulin‑dependent phosphodiesterase and adenylate cyclase; in Design of Enzyme Inhibitors as Drugs, ed. M. Sandler and H.J. Smith, Oxford University Press, New York, pp.650‑697, 1989.
29. Weiss, B., Greenberg, L.H. and Clark, M.B.: Physiological and pharmacological modulation of the beta-adrenergic receptor-linked adenylate cyclase system: supersensitivity and subsensitivity. In: Dynamics of Neurotransmitter Function, ed. I. Hanin, Raven Press, New York, pp.319–330, 1984.
30. Weiss, B. and Costa, E.: Adenyl Cyclase activity in rat pineal gland: Effects of chronic denervation and norepinephrine. Science 156:1750-1752, 1967.
31. Strada, S.J. and Weiss, B.: Increased response to catecholamines of the cyclic AMP system of rat pineal gland induced by decreased sympathetic activity. Arch. Biochem. Biophys. 160:197- 204, 1974.
32. Weiss, B.: Effects of environmental lighting and chronic denervation on the activation of adenyl cyclase of rat pineal gland by norepinephrine and sodium fluoride. J. Pharmacol. Exp. Ther. 168:146-152, 1969.
33. Weiss, B. and Crayton, J.: Gonadal hormones as regulators of pineal adenyl cyclase activity. Endocrinology 87:527-533, 1970.
34. Greenberg, L.H., Dix, R.K. and Weiss, B.: Age-related changes in the binding of dihydroalprenolol in rat brain. In: Pharmacological Intervention in the Aging Process, eds. J. Roberts, R.C. Adelman and V.J. Cristofalo, Plenum Press, New York, pp.245–249, 1978.
35. Greenberg, L.H. and Weiss, B.: Beta adrenergic receptors in aged rat brain: reduced number and capacity of pineal gland to develop supersensitivity. Science 201:61-63, 1978.
36. Weiss, B., Greenberg, L.H. and Cantor, E.: Denervation supersensitivity and beta-adrenergic receptors as a function of age. In: Receptors for Neurotransmitters and Peptide Hormones, eds. G. Pepeu, M.J. Kuhar and S.J. Enna, Raven Press, New York, p 461–472, 1980.
37. Greenberg, L.H. and Weiss, B.: Ability of aged rats to alter beta-adrenergic receptors of brain in response to repeated administration of reserpine and desmethylimipramine. J. Pharmacol. Exp. Ther. 211:309-316, 1979.
38. Strada, S.J., Uzunov, P. and Weiss, B.: Increased sensitivity to norepinephrine (NE) of the cyclic 3',5'-AMP (cAMP) system of rat brain following 6-hydroxydopamine (6-HDM). Pharmacologist 13:257, 1971.
40. Weiss, B. and Greenberg, L.H.: Modulation of beta-adrenergic receptors and calmodulin following acute and chronic treatment with neuroleptics. In: Adv. Biochem. Psychopharmacol., Vol. 24 - Long-Term Effects of Neuroleptics, eds. F. Cattabeni, G. Racagni, P.F. Spano and E. Costa, Raven Press, New York, pp.139–146, 1980.
41. Moyer, J.A., Greenberg, L.H., Frazer, A., Brunswick, D.J., Mendels, J. and Weiss, B.: Opposite effects of acute and repeated administration of desmethylimipramine on adrenergic responsiveness in rat pineal gland. Life Sci. 24:2237-2244, 1979.
43. Zhang, Sui-Po; Long-Wu, Zhou; Weiss, Benjamin (1994). “Oligodeoxynucleotide to the D1 dopamine receptor mRNA inhibits D1 dopamine receptor-mediated behaviors in normal mice and in mice lesioned with 6-hydroxydopamine” J. Pharmacol. Experimental Ther.271(3): 1462- 1470. PMID7996459
44. Weiss, Benjamin; Zhang, Sui-Po; Zhou, Long-Wu (1997) “Antisense strategies in dopamine receptor pharmacology” Life Sciences60(7): 433–455. doi:10.1016/S0024-3205(96)00566-8 PMID9042372
45. Weiss, Benjamin; Davidkova, Genoveva; Zhou, Long-Wu, Zhang, Sui-Po, Morabito, Mark (1997). “Expression of a D2 dopamine receptor antisense RNA in brain inhibits D2-mediated behaviors” Neurochemistry International31(4): 571–580. doi:10.1016/S0197-0186(97)00025-9 PMID9308007
46. Davidkova, Genoveva; Zhou, Long-Wu; Morabito, Mark; Zhang, Sui-Po; Weiss, Benjamin (1998). “D2 dopamine antisense RNA expression vector, unlike haloperidol, produces long-term inhibition of D2 dopamine-mediated behaviors without causing up-regulation of D2 dopamine receptors” J. Pharmacol. Exper. Therapeutics 285(3): 1187–1196.[1]PMID9618422
47. Weiss, Benjamin; Davidkova, Genoveva; Zhou, Long-Wu (1999).”Antisense RNA gene therapy for studying and modulating biological processes” Cell Mol. Life Sci.55(3): 334–358. doi:10.1007/s000180050296 PMID10228554
48. Hou, Wang-Fang; Zhang, Sui-Po; Davidkova, Genoveva; Nichols, Robert; Weiss, Benjamin (1998) “Effects on antisense oligonucleotides directed to individual calmodulin gene transcripts on the proliferation and differentiation of PC12 cells” Antisense Nucleic Acids Drug Dev. 8(4): 295–308. doi:10.1089/oli.1.1998.8.295 PMID9743467
49. Davidkova, Genoveva; Zhang, Sui-Po; Nichols, Robert; Weiss, Benjamin (1996) “Reduced level of calmodulin in PC12 cells induced by stable expression of calmodulin antisense RNA inhibits cell proliferation and induces neurite outgrowth” Neuroscience75(4): 1003–1019. doi:10.1016/0306-4522(96)00230-8 PMID8938737
50. Hait, W.N. and Lazo, J.S.: Calmodulin: a potential target for cancer chemotherapeutic agents. J. Clin. Oncol. 4:994-1012, 1986.
51. Mayur, Y.C., Jagadeesh, S. and Thimmaiah, K.N.: Targeting calmodulin in reversing multi drug resistance in cancer cells. Mini Rev. Med. Chem. 6:1383-1389, 2006.
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