1. Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile 
N. Dietis, R. Guerrini, G. Calo, S. Salvadori, D.J. Rowbotham, D.G. Lambert 
British Journal of Anaesthesia 
Volume 103, Issue 1, Pages (July 2009)
DOI: /bja/aep129
Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

2. Fig 1
Possible mechanisms that can produce two biological effects through two different (and independent) receptors: (1) Drug A and Drug B bind to their respective receptors when administered simultaneously; (2) non-selective ligand C has a structure that promotes binding to both receptors; and (3) a bivalent ligand with two pharmacophores, A and B, binds to two receptors recognized by their active sites. In this simple schema, the two receptors are represented as individual monomers.
British Journal of Anaesthesia  , 38-49DOI: ( /bja/aep129)
Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

3. Fig 2
A schematic and chemical representation of two individual pharmacophoric units. (a) Structures are oxymorphone on the right and naltrindole on the left that can be linked together (b) by an intermediate spacer (linker), in order to produce a molecule with two active sites (valences); a bivalent ligand. The chemical structures were produced using the SureChem software.
British Journal of Anaesthesia  , 38-49DOI: ( /bja/aep129)
Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

4. Fig 3
Schematic representation of possible binding combinations (1–6) to opioid receptor dimers with respective ligands. Two different opioid receptors (blue and orange) constitute a heteromeric receptor dimer. The pharmacophores A and B of the bivalent ligand A–B (see also Fig. 2) are selective for their respective receptors (blue for A, orange for B) and are linked together through an intermediate spacer. When successful binding occurs, an appropriate—but not necessarily identical—response is evoked (represented by the ‘thunderbolt’ sign under the receptors) through activation of G protein. The schema assumes that the G protein associated with each receptor can trigger a response when activated by pharmacophore binding. (1) Bivalent ligand A–B binds to the receptor dimer blue–orange, using both of its pharmacophores for a perfect match. (2) One pharmacophore (A) of the bivalent ligand A–B binds to the respective receptor monomer (blue). (3) Replacement of pharmacophore B with an inactive (+)enantiomer (+B) causes only the binding of pharmacophore A, leaving pharmacophore +B unbound because of its stereochemical divergence. (4) Binding of pharmacophore A, combined with binding of an endogenous opioid ligand C, could possibly leave pharmacophore B unbound. Individual pharmacophore affinities and concentration gradients play a crucial role for the competition of B and C over the red-receptor active site. (5) Two endogenous opioids (D and E) bind to an opioid receptor dimer. The evoked response should theoretically be the same as that from combination-1. (6) Stereochemical orientation bridging of two receptors from neighbouring receptor-dimers is less likely to be successful because of the spatial disorientation of pharmacophores relatively to their active sites. The bivalent ligand A–B cannot take the optimum orientation in order to bridge neighbouring receptors, no matter what rotation its approach takes.
British Journal of Anaesthesia  , 38-49DOI: ( /bja/aep129)
Copyright © 2009 British Journal of Anaesthesia Terms and Conditions

5. Fig 4
Schematic representation of the potential clinical advantages of using bivalent ligands, with the various combinations of pharmacophores (antagonists and agonists). In addition, there are some reports showing reduced tolerance for ligands with mixed MOP/DOP agonist activity.31
British Journal of Anaesthesia  , 38-49DOI: ( /bja/aep129)
Copyright © 2009 British Journal of Anaesthesia Terms and Conditions