Strategy

 
Adrian's strategy for successful drug discovery in neuropsychiatry and neurology is based on close integration of molecular, neurochemical and behavioural pharmacology.
  • Multi-disciplinary characterisation of NCEs.

  • Optimized in vitro screening criteria.

  • Early stage inclusion of whole-animal assays.

  • Thorough candidate profiling before development decisions.


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Areas of Expertise

 

Therapeutic focus: Drug discovery of novel antipsychotics, antidepressants and analgesics.
Neuropharmacology of anxiolytic / anti-stress and anti-Parkinson’s disease agents.

Principal targets: Monoamine receptors and transporters, including serotonin 5‑HT1A and 5-HT2, dopamine D2, D3 and D4 and alpha2 adrenergic receptors. N-Methyl-D-Aspartate (NMDA) receptors.

Specialty areas: Pharmacology of antipsychotics that combine D2 and 5-HT1A receptor properties.
"Biased agonism" or "functional selectivity" of serotonin 5-HT1A and 5-HT2A/2B receptor ligands.

Team management: scientific and administrative responsibility for a multidisciplinary neuropharmacology department (~20 FTEs). “Dotted-line” management of a further dozen pharmacologists in other departments.

Techniques: in vitro binding, signal transduction, autoradiography. Neurochemistry of neurotransmitter release by microdialysis in rodent. Behavioural tests of psychostimulant effects, mood / stress and cognition. Translational models, micro-PET, effects of antipsychotics in dog and non-human primate.

 

Examples of drugs characterised:
  • Milnacipran (Ixel ®, Savella ®): antidepressant and anti-fibromyalgia agent that preferentially inhibits noradrenaline vs serotonin reuptake. Characterisation of analgesic activity and in models of chronic stress.

  • Piribedil (Trivastal ®): antiparkinson agent. Demonstration that it possesses alpha2 adrenoceptor antagonist properties in addition to dopamine D2 receptor partial agonism.

  • Agomelatine (Valdoxan ®): antidepressant agent and melatonin agonist. Demonstration of its antagonist properties at serotonin 5-HT2C and 5-HT2B receptors.

  • Levomilnacipran (Fetzima ®): antidepressant that preferentially inhibits noradrenaline vs serotonin reuptake. Characterisation of in vitro profile and neurochemical activity.

  • Befiradol (=F13640 = NLX-112; Phase II): agonist with high efficacy and selectivity at serotonin 5-HT1A receptors. Potent actvity against L-DOPA-induced dyskinesia in Parkinson's disease.

  • S33138 (Ph.II, discontinued): potential antipsychotic. Characterisation of its preferential dopamine D3 versus D2 receptor affinity and antagonism at these sites. 

  • F15599 (= NLX-101; Ph.I): potential treatment for Rett syndrome and antidepressant. Selective serotonin 5-HT1A receptor 'biased agonist' with preferential activation of receptors in frontal cortex.

  • F15063 (Pre-clinical, discontinued): potential antipsychotic with D2 / D3 antagonism, 5-HT1A and D4 partial agonism. Active in models of positive, negative and cognitive symptoms of schizophrenia.