ABSTRACT
BACKGROUND: An aging society and concomitant rise in the incidence of impaired bone health have led to the need for advanced osteoconductive spinal implant surfaces that promote greater biological fixation (e.g. for interbody fusion cages, sacroiliac joint fusion implants, and artificial disc replacements). Additive manufacturing, i.e. 3D-printing, may improve bone integration by generating biomimetic spinal implant surfaces that mimic bone morphology. Such surfaces may foster an enhanced cellular response compared to traditional implant surfacing processes. METHODS: This study investigated the response of human osteoblasts to additive manufactured (AM) trabecular-like titanium implant surfaces compared to traditionally machined base material with titanium plasma spray (TPS) coated surfaces, with and without a nanocrystalline hydroxyapatite (HA) coating. For TPS-coated discs, wrought Ti6Al4V ELI was machined and TPS-coating was applied. For AM discs, Ti6Al4V ELI powder was 3D-printed to form a solid base and trabecular-like porous surface. The HA-coating was applied via a precipitation dip-spin method. Surface porosity, pore size, thickness, and hydrophilicity were characterized. Initial cell attachment, proliferation, alkaline phosphatase (ALP) activity, and calcium production of hFOB cells (n=5 per group) were measured. RESULTS: Cells on AM discs exhibited expedited proliferative activity. While there were no differences in mean ALP expression and calcium production between TPS and AM discs, calcium production on the AM discs trended 48% higher than on TPS discs (p=0.07). Overall, HA-coating did not further enhance results compared to uncoated TPS and AM discs. CONCLUSIONS: Results demonstrate that additive manufacturing allows for controlled trabecular-like surfaces that promote earlier cell proliferation and trends toward higher calcium production than TPS coating. Results further showed that nanocrystalline HA may not provide an advantage on porous titanium surfaces. CLINICAL RELEVANCE: Additive manufactured porous titanium surfaces may induce a more osteogenic environment compared to traditional TPS, and thus present as an attractive alternative to TPS-coating for orthopedic spinal implants.
ABSTRACT
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Subject(s)
Azabicyclo Compounds/pharmacology , Nicotinic Agonists/pharmacology , Pyridines/pharmacology , Receptors, Nicotinic/drug effects , Animals , Azabicyclo Compounds/chemical synthesis , Azabicyclo Compounds/chemistry , Benzamides/pharmacology , Blood Proteins/drug effects , Bridged Bicyclo Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dogs , Dose-Response Relationship, Drug , Humans , Mice , Microsomes, Liver/drug effects , Molecular Conformation , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Pyridines/chemical synthesis , Pyridines/chemistry , Quinuclidines/pharmacology , Rats , Receptors, Muscarinic/drug effects , Stereoisomerism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.
Subject(s)
Brain/metabolism , Drug Design , Nicotinic Agonists/pharmacology , Receptors, Nicotinic/chemistry , Animals , Bungarotoxins , Cells, Cultured , Electrophysiology , Evoked Potentials, Auditory/drug effects , Hippocampus/drug effects , Ion Channel Gating/drug effects , Molecular Structure , Motor Activity/drug effects , Neurons/drug effects , Nicotinic Agonists/chemical synthesis , Nicotinic Agonists/chemistry , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Synapses/drug effects , Synapses/physiology , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia. Compound 14 is a potent and selective alpha7 nAChR agonist with an excellent in vitro profile. The compound is characterized by rapid brain penetration and high oral bioavailability in rat and demonstrates in vivo efficacy in auditory sensory gating and, in an in vivo model to assess cognitive performance, novel object recognition.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cognition Disorders/drug therapy , Nicotinic Agonists/chemical synthesis , Nootropic Agents/chemical synthesis , Quinuclidines/chemical synthesis , Receptors, Nicotinic/metabolism , Schizophrenia/drug therapy , Animals , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Stability , Ether-A-Go-Go Potassium Channels/drug effects , Evoked Potentials, Auditory/drug effects , Humans , In Vitro Techniques , Learning/drug effects , Male , Memory/drug effects , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Neurons/drug effects , Neurons/physiology , Nicotinic Agonists/pharmacokinetics , Nicotinic Agonists/pharmacology , Nootropic Agents/pharmacokinetics , Nootropic Agents/pharmacology , Patch-Clamp Techniques , Quinuclidines/chemistry , Quinuclidines/pharmacology , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Nicotinic/physiology , Recognition, Psychology/drug effects , Stereoisomerism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
A library of benzamides was tested for alpha7 nicotinic acetylcholine receptor (nAChR) agonist activity using a chimeric receptor in a functional, cell-based, high-throughput assay. From this library, quinuclidine benzamides were found to have alpha7 nAChR agonist activity. The SAR diverged from the activity of this compound class verses the 5-HT(3) receptor, a structural homologue of the alpha7 nAChR. PNU-282987, the most potent compound from this series, was also shown to open native alpha7 nAChRs in cultured rat neurons and to reverse an amphetamine-induced gating deficit in rats.
